Macrocyclic ras inhibitors

Abstract

The disclosure features macrocyclic compounds of formula (la) or (lb), and pharmaceutical compositions and protein complexes thereof, capable of inhibiting Ras proteins, and their uses in the treatment of cancers.

Description

RAS INHIBITORS Background The vast majority of small molecule drugs act by binding a functionally important pocket on a target protein, thereby modulating the activity of that protein. For example, cholesterol-lowering drugs known as statins bind the enzyme active site of HMG-CoA reductase, thus preventing the enzyme from engaging with its substrates. The fact that many such drug / target interacting pairs are known may have misled some into believing that a small molecule modulator could be discovered for most, if not all, proteins provided a reasonable amount of time, effort, and resources. This is far from the case. Current estimates are that only about 10% of all human proteins are targetable by small molecules. Bojadzic and Buchwald, Curr Top Med Chem 18: 674-699 (2019). The other 90% are currently considered refractory or intractable toward above-mentioned small molecule drug discovery. Such targets are commonly referred to as “undruggable.” These undruggable targets include a vast and largely untapped reservoir of medically important human proteins. Thus, there exists a great deal of interest in discovering new molecular modalities capable of modulating the function of such undruggable targets. It has been well established in literature that Ras proteins (K-Ras, H-Ras, and N-Ras) play an essential role in various human cancers and are therefore appropriate targets for anticancer therapy. Indeed, mutations in Ras proteins account for approximately 30% of all human cancers in the United States, many of which are fatal. Dysregulation of Ras proteins by activating mutations, overexpression or upstream activation is common in human tumors, and activating mutations in Ras are frequently found in human cancer. For example, activating mutations at codon 12 in Ras proteins function by inhibiting both GTPase-activating protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly skewing the population of Ras mutant proteins to the “on” (GTP-bound) state (Ras(ON)), leading to oncogenic MAPK signaling. Notably, Ras exhibits a picomolar affinity for GTP, enabling Ras to be activated even in the presence of low concentrations of this nucleotide. Mutations at codons 13 (e.g., G13C) and 61 (e.g., Q61K) of Ras are also responsible for oncogenic activity in some cancers. Despite extensive drug discovery efforts against Ras during the last several decades, only two agents targeting the K-Ras G12C mutant have been approved in the U.S. (sotorasib and adagrasib). Additional efforts are needed to uncover additional medicines for cancers driven by the various Ras mutations. Summary Provided herein are Ras inhibitors. The approach described herein entails formation of a high affinity three-component complex, or conjugate, between a synthetic ligand and two intracellular proteins which do not interact under normal physiological conditions: the target protein of interest (e.g., Ras), and a widely expressed cytosolic chaperone (presenter protein) in the cell (e.g., cyclophilin A). More specifically, in some embodiments, the inhibitors of Ras described herein induce a new binding pocket in Ras by driving formation of a high affinity tri-complex, or conjugate, betweenthe Ras protein and the widely expressed cytosolic chaperone, cyclophilin A (CYPA). Without being bound by theory, the inventors believe that one way the inhibitory effect on Ras is effected by compounds of the invention and the complexes, or conjugates, they form is by steric occlusion of the interaction site between Ras and downstream effector molecules, such as RAF and PI3K, which are required for propagating the oncogenic signal. As such, in an aspect, the disclosure features a compound having the structure of Formula Ia or Formula Ib:, Formula Ia Formula Ib or a pharmaceutically acceptable salt thereof, wherein: Q is an optionally substituted 7- to 12- membered bicyclic arylene, an optionally substituted 7- to 12- membered bicyclic heteroarylene, an optionally substituted 7- to 12- membered bicyclic heterocyclylene, wherein a first ring in Q is bonded to X, and a second ring in Q is bonded to A; X is a bond; a straight chain C1-C3 alkylene optionally substituted with 1 to 3 substituents independently selected from fluoro, -CN, -C1-C3 alkyl, and -O-C1-C3 alkyl; -O-; -S(O)0-2-; *-CH2-O-; *-CH2-S(O)0-2-; *-O-CH2-; or *-CH2-S(O)0-2-, wherein “*” represents a portion of X bound to -C(R7)(R8)-; Y is -O-, -NH- or -N(C1-C3 alkyl)-; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; R3is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, or optionally substituted 3- to 7- membered heterocyclyl; R10is hydrogen, halogen, optionally substituted C1-C3 alkyl, or C1-C3 optionally substituted heteroalkyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8is hydrogen, halogen, -OH, -CN, -O-(optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 4- to 8- membered heteroaryl, optionallysubstituted C3-C6 cycloalkyl, or optionally substituted 3- to 7- membered heterocyclyl; or R7and R8together form =CH2, an optionally substituted C3-C6 cycloalkyl, or a 3- to 7- membered saturated heterocyclyl; or R8and a ring atom in Q, the carbon atom to which R7is bound, and X to form a 4- to 9- membered saturated or unsaturated heterocyclyl that is fused to Q; R6is hydrogen or -CH3; each R5is independently halogen, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 haloalkyl; p is 0, 1, 2, or 3; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl. In an aspect, the invention features a compound having the structure of Formula IIa or Formula IIb:or a pharmaceutically acceptable salt thereof, wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9’, or >CR9R9’where the carbon is bound to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R6)- where C is bound to -C(R7R8)-, -C(O)NH-CH(R6)- where C is bound to -C(R7R8)-, optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is a linker; X3is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; each R’is, independently, hydrogen or optionally substituted C1-C4 alkyl; Y1is C, CH, or N; Y2, Y3, Y4, and Y7are, independently, C or N; Y5is CRx, CH, CH2, or N; Y6is CRz, C(O), CH, CH2, or N; Rxis hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; Rzis hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; R13is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R13and R2combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R2is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R14is absent, or R2and R14combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 heteroalkyl, cyclopropyl, or cyclobutyl; R6is hydrogen or methyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl, orR6and R7combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7and R8combine with the carbon atom to which they are attached to form C=CR7’R8’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7aand R8aare, independently, hydrogen, halogen, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7’is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10- membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7’and R8’combine with the carbon atom to which they are attached to form optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R9and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9’is hydrogen or optionally substituted C1-C6 alkyl; or R9and R9’, combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10is hydrogen, halogen, hydroxy, optionally substituted C1-C3 heteroalkyl, or optionally substituted C1-C3 alkyl; R10ais hydrogen or halogen; R11is hydrogen or optionally substituted C1-C3 alkyl; R21is hydrogen or optionally substituted C1-C3 alkyl; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl.In an aspect, the invention features a compound having the structure of Formula IIa-1:, Formula IIa-1 or a pharmaceutically acceptable salt thereof, wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9’, or >CR9R9’where the carbon is bound to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4heteroalkylene, -C(O)O-CH(R6)- where C is bound to -C(R7R8)-, -C(O)NH-CH(R6)- where C is bound to -C(R7R8)-, optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is a linker; X1is optionally substituted C1-C2 alkylene, NR, O, or S(O)q; X2is O or NH; X3is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; each R’is, independently, hydrogen or optionally substituted C1-C4 alkyl; Y1is C, CH, or N; Y2, Y3, Y4, and Y7are, independently, C or N; Y5is CRx, CH, CH2, or N; Y6is CRz, C(O), CH, CH2, or N;Rxis hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; Rzis hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; R13is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R13and R2combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R2is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R14is absent, or R2and R14combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 heteroalkyl, cyclopropyl, or cyclobutyl; R6is hydrogen or methyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6and R7combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7and R8combine with the carbon atom to which they are attached to form C=CR7’R8’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7aand R8aare, independently, hydrogen, halogen, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7’is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10- membered heteroaryl, or optionally substituted 6- to 10-membered aryl, orR7’and R8’combine with the carbon atom to which they are attached to form optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R9and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9’is hydrogen or optionally substituted C1-C6 alkyl; or R9and R9’, combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10is hydrogen, halogen, hydroxy, optionally substituted C1-C3 heteroalkyl, or optionally substituted C1-C3 alkyl; R10ais hydrogen or halogen; R11is hydrogen or optionally substituted C1-C3 alkyl; and R21is hydrogen or optionally substituted C1-C3 alkyl. In an aspect, the invention features a compound having the structure of Formula IIIa or Formula IIIb:or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene;, , or ; L is a linker; R13is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R10is hydrogen, hydroxy, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7and R8are each, independently, selected from F or CH3, or R7and R8combine with the atoms to which they are attached to make a 3-membered cycloalkyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; t is 0, 1, 2, or 3; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl.In an aspect, the invention features a compound having the structure of Formula IIIa-1:, Formula IIIa-1 or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4alkylene, optionally substituted C1-C4heteroalkylene or optionally substituted C2-C4alkenylene;, , or ; L is a linker; X4and X5are each, independently, CH2, CH(CH3) or NH; R13is optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R10is hydrogen, hydroxy, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;R7and R8are each, independently, selected from F or CH3, or R7and R8combine with the atoms to which they are attached to make a 3-membered cycloalkyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3. In an aspect, the invention features a compound having the structure of Formula IVa or Formula IVb:or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl; R2is optionally substituted C1-C6 alkyl; R3is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; andt is 0, 1, 2, or 3. In an aspect, the invention features a compound having the structure of Formula Va or Formula Vb:, Formula Va Formula Vb or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl; R2is optionally substituted C1-C6 alkyl; R3is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3.In an aspect, the invention features a compound having the structure of Formula VIIa or Formula VIIb:, Formula VIIa Formula VIIb or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; X6, X7, and X8are each independently selected from CH2, CHF, CF2, C=O, or O; m is 1 or 2; n is 0 or 1; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl; R2is optionally substituted C1-C6 alkyl; R3is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3.In an aspect, the invention features a compound having the structure of Formula XI:, Formula XI or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3 to 6- membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5 to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, or optionally substituted C2-C4 alkenylene; W is optionally substituted 3 to 10-membered heterocycloalkyl or optionally substituted 3 to 10-membered cycloalkyl; X4is CH2 or NH; R1is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6- membered cycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 3 to 15-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl; R2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3 to 6- membered cycloalkyl, optionally substituted 3 to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl; and R3is hydrogen; or R2and R3combine, together with the atoms to which they are attached, to form an optionally substituted 8- to 14-membered heterocycloalkyl; each of R4, R5, R6, and R7are hydrogen; or R4and R6are hydrogen and R5and R7combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl; or R5and R7are hydrogen and R4and R6combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl; R10is -OR11or -NR12R13; R11, R12, and R13are each, independently, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or R12and R13combine to form an optionally substituted 3- to 10- membered heterocycloalkyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; andt is 0, 1, 2, or 3. In an aspect, the invention features a compound, or a pharmaceutically acceptable salt thereof, of Table 1. Also provided are pharmaceutical compositions including a compound, or a pharmaceutically acceptable salt thereof, of any of the above aspects and embodiments, and a pharmaceutically acceptable excipient. Also provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. In some embodiments, a method is provided of treating a Ras protein-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. Further provided is a method of inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. It is specifically contemplated that any limitation discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or to utilize any compound or composition of the invention. Definitions and Chemical Terms In this application, unless otherwise clear from context, (i) the term “a” means “one or more”; (ii) the term "or" is used to mean "and / or" unless explicitly indicated to refer to alternatives only or the alternative are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and / or”; (iii) the terms “comprising” and “including” are understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; and (iv) where ranges are provided, endpoints are included. As used herein, the term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value. In certain embodiments, the term “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of a stated value, unless otherwise stated or otherwise evident from the context (e.g., where such number would exceed 100% of a possible value). As used herein, the term “adjacent” in the context of describing adjacent atoms refers to bivalent atoms that are directly connected by a covalent bond. A “compound of the present invention” and similar terms as used herein, whether explicitly noted or not, refers to Ras inhibitors described herein, including compounds of Formula I and subformula thereof, for example, a compound of Table 1, as well as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers thereof.The term “wild-type” refers to an entity having a structure or activity as found in nature in a “normal” (as contrasted with mutant, diseased, altered, etc.) state or context. Those of ordinary skill in the art will appreciate that wild-type genes and polypeptides often exist in multiple different forms (e.g., alleles). Those skilled in the art will appreciate that certain compounds described herein can exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic (e.g., in which one or more atoms has been substituted with a different isotope of the atom, such as hydrogen substituted for deuterium) forms. Unless otherwise indicated or clear from context, a depicted structure can be understood to represent any such isomeric or isotopic form, individually or in combination. Compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, one or more compounds depicted herein may exist in different tautomeric forms. As will be clear from context, unless explicitly excluded, references to such compounds encompass all such tautomeric forms. In some embodiments, tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton. In certain embodiments, a tautomeric form may be a prototropic tautomer, which is an isomeric protonation states having the same empirical formula and total charge as a reference form. Examples of moieties with prototropic tautomeric forms are ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. In some embodiments, tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. In certain embodiments, tautomeric forms result from acetal interconversion. Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36Cl,123I and125I. Isotopically labeled compounds (e.g., those labeled with3H and14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduceddosage requirements). In some embodiments, one or more hydrogen atoms are replaced by2H or3H, or one or more carbon atoms are replaced by13C- or14C-enriched carbon. Positron emitting isotopes such as15O,13N,11C, and18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparations of isotopically labelled compounds are known to those of skill in the art. For example, isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed for compounds of the present invention described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Non-limiting examples of moieties that may contain one or more deuterium substitutions in compounds of the present invention, where any position “R” may be deuterium (D), include., , , , , , , nd VI, and subformulae thereof). Moreover, deuteration of available positions in any A moiety of compounds of the Formulas described herein is also contemplated, such as. Further, deuterium substitution may also take place in compounds of the present invention at the linker position, such as. Further, deuterium substitution may also take place in compounds of the present invention at the linker position, such. Further, deuterium substitution may also take place in compounds of the present invention at the linker position, such. In a further embodiment, silylation substitution is also contemplated, such as in the linker as follows:. As is known in the art, many chemical entities can adopt a variety of different solid forms such as, for example, amorphous forms or crystalline forms (e.g., polymorphs, hydrates, solvate). In some embodiments, compounds of the present invention may be utilized in any such form, including in any solid form. In some embodiments, compounds described or depicted herein may be provided or utilized in hydrate or solvate form. At various places in the present specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-C6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, where a compound includes a plurality of positions at which substituents are disclosed in groups or in ranges, unless otherwise indicated, the present disclosure is intended to cover individual compounds and groups of compounds (e.g., genera and subgenera) containing each and every individual subcombination of members at each position. The term “optionally substituted X” (e.g., “optionally substituted alkyl”) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) per se is optional. As described herein, certain compounds of interest may contain one or more “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent, e.g., any of the substituents or groups described herein. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than onesubstituent selected from a specified group, the substituent may be either the same or different at every position. For example, in the term “optionally substituted C1-C6 alkyl-C2-C9 heteroaryl,” the alkyl portion, the heteroaryl portion, or both, may be optionally substituted. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group may be, independently, deuterium; halogen; -(CH2)0-4R ^; -(CH2)0-4OR ^; -O(CH2)0-4Ro; -O-(CH2)0-4C(O)OR°; -(CH2)0-4CH(OR ^)2; -(CH2)0-4SR ^; -(CH2)0-4Ph, which may be substituted with R°; -(CH2)0-4O(CH2)0-1Ph which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)0-4O(CH2)0-1-pyridyl which may be substituted with R°; 4- to 8-membered saturated or unsaturated heterocycloalkyl (e.g., pyridyl); 3- to 8- membered saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl); -NO2; -CN; -N3; -(CH2)0-4N(R ^)2; -(CH2)0-4N(R ^)C(O)R ^; -N(R ^)C(S)R ^; -(CH2)0-4N(R ^)C(O)NR ^2; -N(R ^)C(S)NR ^2; -(CH2)0-4N(R ^)C(O)OR ^; - N(R ^)N(R ^)C(O)R ^; -N(R ^)N(R ^)C(O)NR ^2; -N(R ^)N(R ^)C(O)OR ^; -(CH2)0-4C(O)R ^; -C(S)R ^; -(CH2)0-4C(O)OR ^; -(CH2)0-4-C(O)-N(Ro)2; -(CH2)0-4-C(O)-N(Ro)-S(O)2-Ro; -C(NCN)NR ^2; -(CH2)0-4C(O)SR ^; -(CH2)0-4C(O)OSiR ^3; -(CH2)0-4OC(O)R ^; -OC(O)(CH2)0-4SR ^; -SC(S)SR°; -(CH2)0-4SC(O)R ^; -(CH2)0-4C(O)NR ^2; -C(S)NR ^2; -C(S)SR°; -(CH2)0-4OC(O)NR ^2; -C(O)N(OR ^)R ^; -C(O)C(O)R ^; -C(O)CH2C(O)R ^; -C(NOR ^)R ^; -(CH2)0-4SSR ^; -(CH2)0-4S(O)2R ^; -(CH2)0-4S(O)2OR ^; -(CH2)0-4OS(O) 2R ^; -S(O)2NR ^2; -(CH2)0-4S(O)R ^; -N(R ^)S(O)2NR ^2; -N(R ^)S(O)2R ^; -N(OR ^)R ^; -C(NOR ^)NR ^2; -C(N H)NR ^2; -P(O)2R ^; -P(O)R ^2; -P(O)(OR ^)2; -OP(O)R ^2; -OP(O)(OR ^)2; -OP(O)(OR ^)R ^; -SiR ^3; -(C1-4 straight or branched alkylene)O-N(R ^)2; or -(C1-4 straight or branched alkylene)C(O)O-N(R ^)2, wherein each R ^ may be substituted as defined below and is independently hydrogen, -C1-6 aliphatic, -CH2Ph, -O(CH2)0-1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ^, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. Suitable monovalent substituents on R ^ (or the ring formed by taking two independent occurrences of R ^ together with their intervening atoms), may be, independently, halogen, -(CH2)0-2R^, -(haloR^), -(CH2)0-2OH, -(CH2)0-2OR^, -(CH2)0-2CH(OR^)2; -O(haloR^), -CN, -N3, -(CH2)0-2C(O)R^, -(CH2)0-2C(O)OH, -(CH2)0-2C(O)OR^, -(CH2)0-2SR^, -(CH2)0-2SH, -(CH2)0-2NH2, -(CH2 )0-2NHR^, -(CH2)0-2NR^2, -NO2, -SiR^3, -OSiR^3, -C(O)SR^, -(C1-4 straight or branched alkylene)C(O)OR^, or -SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected fromC1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R ^ include =O and =S. Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, wherein each independent occurrence of R*is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2-3O-, wherein each independent occurrence of R*is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable substituents on the aliphatic group of R*include halogen, -R^, -(haloR^), -OH, -OR^, -O(haloR^), -CN, -C(O)OH, -C(O)OR^, -NH2, -NHR^, -NR^2, or -NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R†, -NR†2, -C(O)R†, -C(O)OR†, -C(O)C(O)R†, -C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, -C(S)NR†2, -C(NH)NR†2, or -N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable substituents on an aliphatic group of R†are independently halogen, -R^, -(haloR^), -OH, -OR^, -O(haloR^), -CN, -C(O)OH, -C(O)OR^, -NH2, -NHR^, -NR^2, or -NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R†include =O and =S. The term “acetyl,” as used herein, refers to the group -C(O)CH3. The term “alkoxy,” as used herein, refers to a -O-C1-C20 alkyl group, wherein the alkoxy group is attached to the remainder of the compound through an oxygen atom.The term “alkyl,” as used herein, refers to a saturated, straight or branched monovalent hydrocarbon group containing from 1 to 20 (e.g., from 1 to 10 or from 1 to 6) carbons. In some embodiments, an alkyl group is unbranched (i.e., is linear); in some embodiments, an alkyl group is branched. Alkyl groups are exemplified by, but not limited to, methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, and neopentyl. The term “alkylene,” as used herein, represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene, and the like. The term “Cx-Cy alkylene” represents alkylene groups having between x and y carbons. Exemplary values for x are 1, 2, 3, 4, 5, and 6, and exemplary values for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-C6, C1-C10, C2-C20, C2-C6, C2-C10, or C2-C20 alkylene). In some embodiments, the alkylene can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein. The term “alkenyl,” as used herein, represents monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 20 carbons (e.g., from 2 to 6 or from 2 to 10 carbons) containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyls include both cis and trans isomers. The term “alkenylene,” as used herein, represents a divalent straight or branched chain groups of, unless otherwise specified, from 2 to 20 carbons (e.g., from 2 to 6 or from 2 to 10 carbons) containing one or more carbon-carbon double bonds. The term “alkynyl,” as used herein, represents monovalent straight or branched chain groups from 2 to 20 carbon atoms (e.g., from 2 to 4, from 2 to 6, or from 2 to 10 carbons) containing a carbon-carbon triple bond and is exemplified by ethynyl, and 1-propynyl. The term “alkynyl sulfone,” as used herein, represents a group comprising the structure, wherein R is any chemically feasible substituent described herein. The term “amino,” as used herein, represents -N(R†)2, e.g., -NH2 and -N(CH3)2. The term “aminoalkyl,” as used herein, represents an alkyl moiety substituted on one or more carbon atoms with one or more amino moieties. The term “amino acid,” as described herein, refers to a molecule having a side chain, an amino group, and an acid group (e.g., -CO2H or -SO3H), wherein the amino acid is attached to the parent molecular group by the side chain, amino group, or acid group (e.g., the side chain). As used herein, the term “amino acid” in its broadest sense, refers to any compound or substance that can be incorporated into a polypeptide chain, e.g., through formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally-occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L-amino acid. “Standard amino acid” refers to any of the twenty standard L-amino acids commonly found in naturally occurring peptides. Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, optionally substitutedhydroxylnorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine. The term “aryl,” as used herein, represents a monovalent monocyclic, bicyclic, or multicyclic ring system formed by carbon atoms, wherein the ring attached to the pendant group is aromatic. Examples of aryl groups are phenyl, naphthyl, phenanthrenyl, and anthracenyl. An aryl ring can be attached to its pendant group at any heteroatom or carbon ring atom that results in a stable structure and any of the ring atoms can be optionally substituted unless otherwise specified. The term “C0,” as used herein, represents a bond. For example, part of the term -N(C(O)-(C0-C5 alkylene-H)- includes -N(C(O)-(C0 alkylene-H)-, which is also represented by -N(C(O)- H)-. The terms “carbocyclic” and “carbocyclyl,” as used herein, refer to a monovalent, optionally substituted C3-C12 monocyclic, bicyclic, or tricyclic ring structure, which may be bridged, fused or spirocyclic, in which all the rings are formed by carbon atoms and at least one ring is non-aromatic. Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups are cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indanyl, decalinyl, and the like. A carbocyclic ring can be attached to its pendant group at any ring atom that results in a stable structure and any of the ring atoms can be optionally substituted unless otherwise specified. The term “carbonyl,” as used herein, represents a C(O) group, which can also be represented as C=O. The term “carboxyl,” as used herein, means -CO2H, (C=O)(OH), COOH, or C(O)OH or the unprotonated counterparts. The term “cyano,” as used herein, represents a -CN group. The term “cycloalkyl,” as used herein, represents a monovalent saturated cyclic hydrocarbon group, which may be bridged, fused or spirocyclic having from three to eight ring carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl. The term “cycloalkenyl,” as used herein, represents a monovalent, non-aromatic, saturated cyclic hydrocarbon group, which may be bridged, fused or spirocyclic having from three to eight ring carbons, unless otherwise specified, and containing one or more carbon-carbon double bonds. The term “diastereomer,” as used herein, means stereoisomers that are not mirror images of one another and are non-superimposable on one another. The term “enantiomer,” as used herein, means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%. The term “guanidinyl,” refers to a group having the structure:, wherein each R is, independently, any any chemically feasible substituent described herein.The term “guanidinoalkyl alkyl,” as used herein, represents an alkyl moiety substituted on one or more carbon atoms with one or more guanidinyl moieties. The term “haloacetyl,” as used herein, refers to an acetyl group wherein at least one of the hydrogens has been replaced by a halogen. The term “haloalkyl,” as used herein, represents an alkyl moiety substituted on one or more carbon atoms with one or more of the same of different halogen moieties. The term “halogen,” as used herein, represents a halogen selected from bromine, chlorine, iodine, or fluorine. The term "heteroalkyl,” as used herein, refers to an "alkyl" group, as defined herein, in which at least one carbon atom has been replaced with a heteroatom (e.g., an O, N, or S atom). The heteroatom may appear in the middle or at the end of the radical. The term “heteroaryl,” as used herein, represents a monovalent, monocyclic, or polycyclic ring structure that contains at least one fully aromatic ring: i.e., they contain 4n+2 pi electrons within the monocyclic or polycyclic ring system and contains at least one ring heteroatom selected from N, O, or S in that aromatic ring. Exemplary unsubstituted heteroaryl groups are of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term “heteroaryl” includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heteroaromatic rings is fused to one or more, aryl or carbocyclic rings, e.g., a phenyl ring, or a cyclohexane ring. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindolyl. A heteroaryl ring can be attached to its pendant group at any ring atom that results in a stable structure and any of the ring atoms can be optionally substituted unless otherwise specified. In some embodiments, the heteroaryl is substituted with 1, 2, 3, or 4 substituents groups. The term “heterocycloalkyl,” as used herein, represents a monovalent monocyclic, bicyclic, or polycyclic ring system, which may be bridged, fused or spirocyclic, wherein at least one ring is non- aromatic and wherein the non-aromatic ring contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The 5-membered ring has zero to two double bonds, and the 6- and 7-membered rings have zero to three double bonds. Exemplary unsubstituted heterocycloalkyl groups are of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term “heterocycloalkyl” also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group. The term “heterocycloalkyl” includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, a pyridine ring, or a pyrrolidine ring. Examples of heterocycloalkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronapthyridinyl. A heterocycloalkyl ring can be attached to its pendant group at any ring atom that results in a stable structure and any of the ring atoms can be optionally substituted unless otherwise specified. The term “hydroxy,” as used herein, represents a -OH group.The term “hydroxyalkyl,” as used herein, represents an alkyl moiety substituted on one or more carbon atoms with one or more -OH moieties. The term “isomer,” as used herein, means any tautomer, stereoisomer, atropisomer, enantiomer, or diastereomer of any compound of the invention. It is recognized that the compounds of the invention can have one or more chiral centers or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric E / Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). According to the invention, the chemical structures depicted herein, and therefore the compounds of the invention, encompass all the corresponding stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates. Enantiomeric and stereoisomeric mixtures of compounds of the invention can typically be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods. As used herein, the term “linker” refers to a divalent organic moiety connecting a first moiety (e.g., one portion of a macrocycle) to a second moiety (e.g., a second portion of the same macrocycle). In some embodiments, the linker results in a compound capable of achieving an IC50 of 2 µM or less in the Ras-RAF disruption assay protocol provided here: The purpose of this biochemical assay is to measure the ability of test compounds to facilitate ternary complex formation between a nucleotide-loaded Ras isoform and cyclophilin A; the resulting ternary complex disrupts binding to a BRAFRBDconstruct, inhibiting Ras signaling through a RAF effector. In assay buffer containing 25 mM HEPES pH 7.3, 0.002% Tween20, 0.1% BSA, 100 mM NaCl and 5 mM MgCl2, tagless cyclophilin A, His6-K-Ras-GMPPNP (or other Ras variant), and GST-BRAFRBDare combined in a 384-well assay plate at final concentrations of 25 µM, 12.5 nM and 50 nM, respectively. Compound is present in plate wells as a 10-point 3-fold dilution series starting at a final concentration of 30 µM. After incubation at 25oC for 3 hours, a mixture of Anti-His Eu-W1024 and anti-GST allophycocyanin is then added to assay sample wells at final concentrations of 10 nM and 50 nM, respectively, and the reaction incubated for an additional 1.5 hours. TR-FRET signal is read on a microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that facilitate disruption of a Ras:RAF complex are identified as those eliciting a decrease in the TR-FRET ratio relative to DMSO control wells. This assay may be used to assess selectivity as well. In some embodiments, a compound of the present invention is selective for one or more particular Ras mutants over other Ras mutants or wild- type compared to what is known in the art. For example, a compound of Formula Ia and subformulae thereof may be more selective for K-Ras G12C or K-Ras G13C compared to K-Ras wild-type. For example, a compound of Formula IIa-1 and Formula IIa-2 may be more selective for K-Ras G12C, K- Ras G13C, K-Ras G12D or K-Ras G12V compared to K-Ras wild-type. For example, a compound ofFormula IIIa-1 and Formula IIIa-2 may be more selective for K-Ras G12D or K-Ras G12V compared to K-Ras wild-type. For example, a compound of Formula IVa and subformulae thereof may be more selective for K-Ras G12C or K-Ras G13C compared to K-Ras wild-type. For example, a compound of Formula VIa and subformulae thereof may be more selective for K-Ras G12D compared to K-Ras wild-type. For example, a compound of Formula VIIa and subformulae thereof may be more selective for K-Ras G12D compared to K-Ras wild-type. Without being bound by theory, the inventors postulate that non-covalent interactions of “L” and the chaperone protein (e.g., cyclophilin A) may contribute to the inhibition of Ras activity. For example, van der Waals, hydrophobic, hydrophilic and hydrogen bond interactions, and combinations thereof, may contribute to the ability of the compounds of the present invention to form complexes and act as Ras inhibitors. The inventors also postulate that “L” also imparts structural rigidity to the compounds, which may optimize these non-covalent interactions, thereby contributing to the inhibition of Ras activity. In some embodiments, the linker comprises 20 or fewer linear atoms. In some embodiments, the linker comprises 15 or fewer linear atoms. In some embodiments, the linker comprises 10 or fewer linear atoms. In some embodiments, the linker has a molecular weight of under 500 g / mol. In some embodiments, the linker has a molecular weight of under 400 g / mol. In some embodiments, the linker has a molecular weight of under 300 g / mol. In some embodiments, the linker has a molecular weight of under 200 g / mol. In some embodiments, the linker has a molecular weight of under 100 g / mol. In some embodiments, the linker has a molecular weight of under 50 g / mol. As used herein, a “monovalent organic moiety” is less than 500 kDa. In some embodiments, a “monovalent organic moiety” is less than 400 kDa. In some embodiments, a “monovalent organic moiety” is less than 300 kDa. In some embodiments, a “monovalent organic moiety” is less than 200 kDa. In some embodiments, a “monovalent organic moiety” is less than 100 kDa. In some embodiments, a “monovalent organic moiety” is less than 50 kDa. In some embodiments, a “monovalent organic moiety” is less than 25 kDa. In some embodiments, a “monovalent organic moiety” is less than 20 kDa. In some embodiments, a “monovalent organic moiety” is less than 15 kDa. In some embodiments, a “monovalent organic moiety” is less than 10 kDa. In some embodiments, a “monovalent organic moiety” is less than 1 kDa. In some embodiments, a “monovalent organic moiety” is less than 500 g / mol. In some embodiments, a “monovalent organic moiety” ranges between 500 g / mol and 500 kDa. The term “stereoisomer,” as used herein, refers to all possible different isomeric as well as conformational forms which a compound may possess (e.g., a compound of any formula described herein), in particular all possible stereochemically and conformationally isomeric forms, all diastereomers, enantiomers or conformers of the basic molecular structure, including atropisomers. Some compounds of the present invention may exist in different tautomeric forms, all of the latter being included within the scope of the present invention. The term “sulfonyl,” as used herein, represents an -S(O)2- group. The term “thiocarbonyl,” as used herein, refers to a -C(S)- group.The term “vinyl ketone,” as used herein, refers to a group comprising a carbonyl group directly connected to a carbon-carbon double bond. The term “vinyl sulfone,” as used herein, refers to a group comprising a sulfonyl group directed connected to a carbon-carbon double bond. The term “ynone,” as used herein, refers to a group comprising the structure, wherein R is any any chemically feasible substituent described herein. Those of ordinary skill in the art, reading the present disclosure, will appreciate that certain compounds described herein may be provided or utilized in any of a variety of forms such as, for example, salt forms, protected forms, pro-drug forms, ester forms, isomeric forms (e.g., optical or structural isomers), isotopic forms, etc. In some embodiments, reference to a particular compound may relate to a specific form of that compound. In some embodiments, reference to a particular compound may relate to that compound in any form. In some embodiments, for example, a preparation of a single stereoisomer of a compound may be considered to be a different form of the compound than a racemic mixture of the compound; a particular salt of a compound may be considered to be a different form from another salt form of the compound; a preparation containing one conformational isomer ((Z) or (E)) of a double bond may be considered to be a different form from one containing the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form. Detailed Description Compounds Provided herein are Ras inhibitors. The approach described herein entails formation of a high affinity three-component complex, or conjugate, between a synthetic ligand and two intracellular proteins which do not interact under normal physiological conditions: the target protein of interest (e.g., Ras), and a widely expressed cytosolic chaperone (presenter protein) in the cell (e.g., cyclophilin A). More specifically, in some embodiments, the inhibitors of Ras described herein induce a new binding pocket in Ras by driving formation of a high affinity tri-complex, or conjugate, between the Ras protein and the widely expressed cytosolic chaperone, cyclophilin A (CYPA). Without being bound by theory, the inventors believe that one way the inhibitory effect on Ras is effected by compounds of the invention and the complexes, or conjugates, they form is by steric occlusion of the interaction site between Ras and downstream effector molecules, such as RAF, which are required for propagating the oncogenic signal. Without being bound by theory, the inventors postulate that covalent, non-covalent or combinations of covalent and non-covalent interactions of a compound of the present invention with Ras and the chaperone protein (e.g., cyclophilin A) may contribute to the inhibition of Ras activity. In some embodiments, a compound of the present invention forms a covalent adduct with a side chain of a Ras protein (e.g., a side chain of the histidine at position 61 of a mutant Ras protein). Covalent adducts may also be formed with other side chains of Ras. In addition, or alternatively, non-covalentinteractions may be at play: for example, van der Waals, hydrophobic, hydrophilic and hydrogen bond interactions, and combinations thereof, may contribute to the ability of the compounds of the present invention to form complexes and act as Ras inhibitors. Accordingly, a variety of Ras proteins may be inhibited by a compound of the present invention (e.g., K-Ras, N-Ras, H-Ras, and mutants thereof at positions 12, 13 and 61, such as G12C, G12D, G12V, G12S, G13C, G13D, Q61H, Q61K, Q61R and Q61L, and others described herein, or a combination thereof). Methods of determining covalent adduct formation are known in the art. One method of determining covalent adduct formation is to perform a “cross-linking” assay, such as under these conditions. Note – the following protocol describes a procedure for monitoring cross-linking of K-Ras G12C (GMP-PNP) to a compound of the invention. This protocol may also be executed substituting other Ras proteins or nucleotides. The purpose of this biochemical assay is to measure the ability of test compounds to covalently label nucleotide-loaded K-Ras isoforms. In assay buffer containing 12.5 mM HEPES pH 7.4, 75 mM NaCl, 1 mM MgCl2, 1 mM BME (if studying a cysteine Ras mutant, such as K-Ras G12C or G13C), 5 µM cyclophilin A and 2 µM test compound, a 5 µM stock of GMP-PNP-loaded K-Ras (1-169) G12C is diluted 10-fold to yield a final concentration of 0.5 µM; with final sample volume being 100 µL. The sample is incubated at 25 °C for a time period of up to 24 hours prior to quenching by the addition of 10 µL of 5% Formic Acid. Quenched samples are centrifuged at 15000 rpm for 15 minutes in a benchtop centrifuge before injecting a 10 µL aliquot onto a reverse phase C4 column and eluting into the mass spectrometer with an increasing acetonitrile gradient in the mobile phase. Analysis of raw data may be carried out using Waters MassLynx MS software, with % bound calculated from the deconvoluted protein peaks for labeled and unlabeled K- Ras. Accordingly, provided herein is a compound having the structure of Formula Ia or Formula Ib:, Formula Ia Formula Ib or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein:Q is an optionally substituted 7- to 12- membered bicyclic arylene, an optionally substituted 7- to 12- membered bicyclic heteroarylene, an optionally substituted 7- to 12- membered bicyclic heterocyclylene, wherein a first ring in Q is bonded to X, and a second ring in Q is bonded to A; X is a bond; a straight chain C1-C3 alkylene optionally substituted with 1 to 3 substituents independently selected from fluoro, -CN, -C1-C3 alkyl, and -O-C1-C3 alkyl; -O-; -S(O)0-2-; *-CH2-O-; *-CH2-S(O)0-2-; *-O-CH2-; or *-CH2-S(O)0-2-, wherein “*” represents a portion of X bound to -C(R7)(R8)-; Y is -O-, -NH- or -N(C1-C3 alkyl)-; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; R3is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, or optionally substituted 3- to 7- membered heterocyclyl; R10is hydrogen, halogen, optionally substituted C1-C3 alkyl, or C1-C3 optionally substituted heteroalkyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8is hydrogen, halogen, -OH, -CN, -O-(optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 4- to 8- membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7- membered heterocyclyl; or R7and R8together form =CH2, an optionally substituted C3-C6 cycloalkyl, or a 3- to 7- membered saturated heterocyclyl; or R8and a ring atom in Q, the carbon atom to which R7is bound, and X to form a 4- to 9- membered saturated or unsaturated heterocyclyl that is fused to Q; R6is hydrogen or -CH3; each R5is independently halogen, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 haloalkyl; p is 0, 1, 2, or 3; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl.In some embodiments, the compound has the structure of Formula Ia-1:Formula Ia-1 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein Q is an optionally substituted 7- to 12-membered bicyclic arylene, an optionally substituted 7- to 12-membered bicyclic heteroarylene, an optionally substituted 7- to -12 membered bicyclic heterocyclylene, wherein a first ring in Q is bonded to X, and a second ring in Q is bonded to A; X is a bond; a straight chain C1-C3 alkylene optionally substituted with 1 to 3 substituents independently selected from fluoro, -CN, -C1-C3 alkyl, and -O-C1-C3 alkyl; -O-; -S(O)0-2-; *-CH2-O-; *-CH2-S(O)0-2-; *-O-CH2-; or *-CH2-S(O)0-2-, wherein “*” represents a portion of X bound to -C(R7)(R8)-; Y is -O-, -NH- or -N(C1-C3 alkyl)-; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; R3is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, or optionally substituted 3- to 7-membered heterocyclyl; R10is hydrogen, halogen, optionally substituted C1-C3 alkyl, C1-C3 optionally substituted heteroalkyl, or C1-C3 optionally substituted hydroxyalkyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8is hydrogen, halogen, -OH, -CN, -O-(optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7-membered heterocyclyl; or R7and R8are taken together to form =CH2, an optionally substituted C3-C6 cycloalkyl, or a 3- to 7- membered saturated heterocyclyl; or R8is taken together with a ring atom in Q, the carbon atom to which R7is bound and X to form a 4- to 9-membered saturated or unsaturated heterocyclyl that is fused to Q; R6is hydrogen or -CH3;each R5is independently halogen, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 haloalkyl; and p is 0, 1, 2, or 3. In some embodiments, the compound has the structure of formula Ia-2:Formula Ia-2, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. where: X is a bond, -O-, -CH2-, -CH(CH3)-, *-CH2-O-, or -CH2-CH2-, where “*” represents a portion of X bound to C(R4)(R5); Y is -O- or -NH-; L is a linker; R3is -C1-C4 alkyl, -(CH2)0-1-(C3-C6 cycloalkyl), or -C4-C6 cycloalkyl; R7is hydrogen, halo, or C1-C3 alkyl; R8is hydrogen, halo, -OH, C1- C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkylene-O-C1-C3 alkyl, C1-C3 haloalkyl, -(CH2)0-1-C3-C6 cycloalkyl, C1-C3 cyanoalkyl, or -(CH2)0-1-aryl (benzyl), or R7and R8are taken together to form =CH2, or a C3-C6 cycloalkyl, or R8is taken together with a ring atom of Q, the carbon atom to which it is bound and X to form a 5- to 7-membered saturated heterocyclyl; Q is a bicyclic arylene, a bicyclic heteroarylene, or a bicyclic heterocyclylene, where: a first ring in Q is bonded to X, and a second ring in Q is bonded Z; and Q is optionally substituted with one or more independently selected substituents selected from =O; -CN; halogen; -C1-C5 alkyl optionally substituted with one or more independently selected halo, CN, OH, -O-(C1-C3 alkyl), -C(O)-(C1-C3 alkyl), -O-(C2-C3 alkynyl), -(C3-C6 cycloalkyl), or a 4- to 7- membered saturated heterocyclyl; -O-(C1-C3 alkyl) optionally substituted with one or more independently selected halo; C2-C5 alkenyl optionally substituted with one or more independently selected -CN, or -OH; C2-C3 alkynyl; -S(O)2-C1-C3 alkyl; -(CH2)0-1-C3-C6 cycloalkyl optionally substituted with one or more independently selected halo, =O, -CN, C1-C3 alkyl optionally substituted with -CN or -O-C1-C3 alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -O-aryl; -(CH2)0-1-heteroaryl optionally substituted with one or more independently selected halo, -CN, C1-C3 alkyl optionally substituted with -CN or -O-C1-C3 alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -O-aryl; -(CH2)0-1-heterocyclyl optionally substituted with one or more independently selected halo, =O, -CN, C1-C3 alkyl optionally substitutedwith -CN or -O-C1-C3 alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -O-aryl; -(CH2)0-1-aryl optionally substituted with one or more independently selected halo, -CN, -C1-C3 alkyl optionally substituted with -CN or -O-C1-C3 alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -O-aryl; -C(O)-NH-(C1-C3 alkyl); -C(O)-N(C1-C3 alkyl)2; C2-C3 alkenylene=N-O-(C1-C3 alkyl) optionally substituted with C3-C6 cycloalkyl; or two substituents on the same or adjacent ring atoms of Q are taken together to form a 5- to 7- membered monocyclic ring or a 6- to 12-membered bicyclic ring optionally substituted with one or more independently selected halo, =O, -CN, C1-C3 alkyl, or -O-C1-C3 alkyl; and fused to Q. In some embodiments, the compound has the structure of formula Ia-3:Formula Ia-3, or a pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of formula (Ic):pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, Q is a 5,6 bicyclic heteroarylene, a 5,6 bicyclic heterocyclylene, a 6,6 bicyclic heteroarylene, or a 6,6 bicyclic heterocyclylene; and where Q is optionally substituted. In some embodiments, Q is a 5,6 bicyclic heteroarylene, wherein Q is optionally substituted. In some embodiments, Q is a 5,6 bicyclic heterocyclylene, wherein Q is optionally substituted. In some embodiments, Q is a 6,6 bicyclic heteroarylene, wherein Q is optionally substituted. In some embodiments, Q is a 6,6 bicyclic heterocyclylene, wherein Q is optionally substituted.In some embodiments, Q is selected from the group consisting of:, wherein: each of V1, V2, V3 and V4 is independently C, CH, CF, or N; RQ1is -S(O)2-RQ11, - C(O)-RQ11, -S(O)2-N(RQ11)RQ12, -C(O)-N(RQ11)RQ12, C1-C10alkyl, C3-C10cycloalkyl, a 4- to 14-membered heterocyclyl, aryl, or heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted; or RQ1is taken together with the nitrogen atom to which it is attached and an adjacent ring atom to form an optionally substituted 4- to 8-membered ring, which is optionally further fused to a 5- to 6- membered ring; each of RQ11and RQ12is independently C1-C10 alkyl, C3-C10 cycloalkyl, a 4- to 14-membered heterocyclyl, aryl, or heteroaryl, where each of RQ11and RQ12is optionally substituted; or RQ11and RQ12are taken together with the nitrogen atom to which they are both attached to form an optionally substituted 4- to 8-membered ring, where the ring formed by taking RQ11and RQ12together is optionally fused to another 5- to 6-membered ring. In some embodiments, Q is optionally additionally substituted with 1 to 4 substituents independently selected from =O; halo; -OH; -CN; -C1-C5 alkyl optionally substituted with one or more independently selected halo, CN, OH, -O-(C1-C3 alkyl), -C(O)-(C1-C3 alkyl), -O-C(O)-N(C1-C3 alkyl)2, -O-(C2-C3 alkynyl), -(C3-C6 cycloalkyl), a 5- to 6-membered heteroaryl optionally substituted with one or more C1-C3 alkyl, or a 4- to 7-membered saturated heterocyclyl; -O-(C1-C3 alkyl) optionally substituted with one or more independently selected halo; -C2-C5 alkenyl optionally substituted with one or more independently selected -CN, or -OH; C2-C3 alkynyl optionally substituted with a heteroaryl; -S(O)2-C1-C3 alkyl; -(CH2)0-1-C3-C6 cycloalkyl optionally substituted with one or moreindependently selected halo, =O, -CN, C1-C3 alkyl optionally substituted with -CN or -O-C1-C3 alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -O-aryl; -(CH2)0-1-heteroaryl optionally substituted with one or more independently selected halo, -CN, C1-C3 alkyl optionally substituted with -CN or -O-C1-C3 alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -O-aryl; -(CH2)0-1-heterocyclyl optionally substituted with one or more independently selected halo, =O, -CN, C1-C3 alkyl optionally substituted with -CN or -O-C1-C3 alkyl, -C(O)-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -O-aryl; -(CH2)0-1-aryl optionally substituted with one or more independently selected halo, -CN, -C1-C3 alkyl optionally substituted with -CN, -C(O)-O-C1-C3 alkyl, -C1-C3 alkylene-O-C1-C3 alkyl, -O-C1-C3 alkyl, NO2, -C(O)-saturated heterocyclyl, -CH2-saturated heterocyclyl, -O-saturated heterocyclyl, O-cycloalkyl, or -O-aryl; -CH2-O-heteroaryl, -C(O)-NH-(C1-C3 alkyl); -C(O)-N(C1-C3 alkyl)2; C2-C3 alkenylene=N-O-(C1-C3 alkyl) optionally substituted with C3-C6 cycloalkyl; or two substituents on Q are taken together to form a 5- to 7-membered monocyclic ring or a 6- to 12-membered bicyclic ring optionally substituted with one or more independently selected halo, =O, -CN, C1-C3 alkyl, or -O-C1-C3 alkyl, and fused to Q; and “**” represents a portion of Q that is bound to ring Z.. In some embodiments, Q is In some embodiments,some embodiments, Q isIn some embodiments, Q is optionally additionally substituted with 1 to 4 substituents independently selected from chloro, fluoro, -CN, -CH3, -CF3, -CHF2, -CH2CH3, -CH2-CN, -(CH2)2-CN, -OCH3, -CH2-O-CH3, -(CH2)2-O-CH3, -CH2-O-CH2-CN, -CH(CN)-CH3, -C(O)-N(CH3)2, -C(O)-NH-CH3, -C(O)-CH3, -S(O)2CH3, -C(CH3)=N-O- CH(CH3)2, -C(CH3)=N-O-CH3, -C≡C-CH3, -C≡CH, -CH=CH-CN, -CH2-O-CH2-C≡CH, -C(CH3)(CN)CH2 CN, -CH2-O-C(O)-N(CH3)2, 1-(cyclopentyl)-1-cyanoethan-1-yl, 1-(tetrahydrofuran-3-yl)-1-cyanoethan-1-yl, 1-(tetrahydropyran-4-yl)-1-cyanoethan-1-yl, 1,3-dimethoxy-2-cyanopropan-2-yl, 1,4-dimethylpyrazol-5-yl, 1-cyanocyclobutyl, 1-cyanocyclopropyl, 1-cyanocylopentyl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 1-methylpiperidin-4-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-5-yl, (1-methylpyrazol-4-yl)cyanomethyl, 1-oxoindolin-5-yl, 1-oxoisoindolin-4-yl, 1-oxoisoindolin-6-yl, 2-(2-methoxyethan-1-yl)phenyl, 3-(1,1-dioxothiomorpholin-1-ylmethyl)phenyl, 2-(tetrahydropyran-4-yloxy)phenyl, 2,2-difluoro-benzo[d][1,3]dioxol-4-yl, 2-chlorophenyl, 2-cyano-2-tetrahydrofuran-3-ylpropanyl, 2-cyano-3-chlorophenyl, 2-cyano-3-fluorophenyl, 2-cyano-3-methoxyphenyl, 2-cyano-4-fluorophenyl, 2-cyano-4-chlorophenyl, 2-cyano-4-methoxybutan-2-yl, 2-cyano-5-chlorophenyl, 2-cyano-5-fluorophenyl, 2-cyano-5-methoxyphenyl, 2-cyano-5-(methoxymethyl)phenyl, 2-cyano-6-chlorophenyl, 2-cyano-6-fluorophenyl, 2-cyano-6-bromophenyl, 2-cyano-6-(methoxymethyl)phenyl, 2-cyano-6-(tetrahydropyran-4-yloxy)phenyl, 2-cyanomethylphenyl, 2-cyanophenyl, 2-cyanopropan-2-yl, 2-cyclopentylphenyl, 2-difluoromethoxyphenyl, 2-fluorophenyl, 2-methoxy-6-cyanophenyl, 2-methoxyphenyl, 2-methoxycarbonylphenyl, 2-(methoxymethyl)phenyl, 2-nitrophenyl, 2-oxopyrrolidin-1-yl, 2-phenoxyphenyl, 3-(2-methoxyethan-1-yl)phenyl, 3-methoxycarbonylphenyl, 3,5-difluoro-4-(pyrrolidin-1-ylcarbonyl)phenyl, 3-cyano-2-methylpropan-2-yl, 3-cyanomethylphenyl, 3-cyanopentan-3-yl , 3-cyanophenyl,3-hydroxy-2-methylbutan-2-yl, 3-hydroxy-3-methyl-but-1-yne-1-yl, 3-methoxy-2-methylbutan-2-yl, 3-methoxyphenyl, 3-methoxymethyl-5-methylisoxazol-4-yl, 3-oxo-2-methylbutan-2-yl, 3-(tetrahydropyran-4-yl)-2-cyanopropan-2-yl, 4-cyanophenyl, 4-cyanotetrahydropyran-4-yl, 4-methoxyphenyl, benzo[d][1,3]dioxol-4-yl, benzo[d]oxazol-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, cyclobutyl, cyclopropyl, cyclopropylcyanomethyl, morpholin-4-ylmethyl, N-methoxycyclopropanecarbimidoyl, phenyl, pyrazol-1-ylmethyl, pyridin-2-yl, pyridin-2-ylmethyl, pyridin-2-yloxymethyl, pyridin-3-yl, pyridin-3-yl-ethynyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyridin-4-yl-ethynyl, tetrahydrofuran-3-ylmethyl, tetrahydrofuran-3-ylcyanomethyl, tetrahydropyridin-4-yl, tetrahydropyran-4-ylmethyl, 2-(tetrahydropyran-4-yl)ethan-1-yl, tetrahydropyran-4-ylcyanomethyl, or tetrahydropyran-4-yl, or two substituents attached to the same carbon atom are taken together to form =O, 2,3-dihydrobenzofuran-3,3-diyl, 2,3-dihydrofuro[2,3-b]pyridin-3,3-diyl, tetrahydropyran-3,3-diyl, 6,7-dihydro-5H-cyclopenta[c]pyridin-6,6-diyl, or tetrahydropyran-4,4-diyl, or two substituents attached to adjacent carbon atoms are taken together to form 4-cyanobenzene-1,2-diyl, 3-cyanobenzene-1,2-diyl, 5-methyl-5-cyanotetrahydropyran-3,4-diyl, 3-cyanocyclohexan-1,2-diyl, 3-methoxybenzene-1,2-diyl, benzene-1,2-diyl, 3-oxocyclohexyl-1,2-diyl, 3-cyanocyclopentan-1,2-diyl, or pyridin-3,4-diyl. In some embodiments, Q is selected from the group consisting of: ,wherein: each of V1, V2, V3 and V4 is independently CH, N, C(F), C(CH3), C(OH), C(OCH3), or C(CN);each of V5, V6, and V7 is independently, C(R17a)(R17b), or C(=O), where each of R17aand R17bis independently selected from hydrogen, halo, -C1-C3 alkyl, -C1-C3 haloalkyl, -O-C1-C3 alkyl, -O-C1-C3 haloalkyl, and no more than two of V5, V6, and V7 is C(=O); RNQ1is hydrogen, optionally substituted -S(O)2-RQ11, - C(O)-RQ11, -S(O)2-N(RQ11)RQ12, -C(O)-N(RQ11)RQ12, C1-C10 alkyl, C3-C10 cycloalkyl, a 4- to 14-membered heterocyclyl, aryl, or heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted; each RQ2is independently hydrogen, CN, optionally substituted -S(O)2-RQ11, - C(O)-RQ11, -S(O)2-N(RQ11)RQ12, -C(O)-N(RQ11)RQ12, C1-C10 alkyl, C3-C10 cycloalkyl, a 4- to 14-membered heterocyclyl, aryl, or heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted; or RNQ1and one RQ2are taken together with the atoms to which they are bound to form an optionally substituted 4- to 8-membered ring, where the ring formed by taking RNQ1and one RQ2together is optionally further fused to a 5- to 6-membered ring; each RQ3is independently hydrogen, CN, optionally substituted -S(O)2-RQ11, - C(O)-RQ11, -S(O)2-N(RQ11)RQ12, -C(O)-N(RQ11)RQ12, C1-C10 alkyl, C3-C10 cycloalkyl, a 4-14 membered heterocyclyl, aryl, or heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted, or two RQ3bound to the same atom are taken together to form =CH, =O, =S, or =NRV4; or two RQ3bound to the same atom are taken together with the atom to which they are bound to form an optionally substituted 4- to 8-membered ring, where the ring formed by taking each RQ3together is optionally further fused to a 5- to 6-membered ring; or RNQ1and one RQ3are taken together with the atoms to which they are bound to form an optionally substituted 4- to 8-membered ring, where the ring formed by taking RNQ1and RQ3together is optionally further fused to a 5- to 6-membered ring; each of RQ11and RQ12is independently C1-C10 alkyl, C3-C10 cycloalkyl, a 4- to 14-membered heterocyclyl, aryl, or heteroaryl, where each of RQ11and RQ12is optionally substituted; or RQ11and RQ12are taken together with the atoms to which they are attached to form an optionally substituted 4- to 8-membered ring, where the ring formed by taking RQ11and RQ12together is optionally fused to another 5- to 6-membered ring; and “**” represents a portion of Q that is bound to ring Z. In some embodiments, Q is,some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q isIn some embodiments, Q is . In some embodiments, Q isIn some embodiments, Q is selected from the group consisting of:so e e o e s, s . In some embodiments, the compound has the structure of formula (Id):pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of formula (Ie):pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of formula (Ig):pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, where Qais a 4- to 9-membered saturated heterocyclyl. In some embodiments, the compound has the structure of formula (Ij):pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of formula (Ik):pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of formula (Ik’):pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, Q is selected from the group consisting of:, , , ,wherein: “1” indicates a portion of Q bound to X; and Q is further optionally substituted. In some embodiments,some embodiments,some embodiments,someembodiments,some embodiments,someembodiments, Q is . In some embodiments, Q is. In some embodiments, Q is. In some embodiments,some embodiments, Q is In some embodiments,some embodiments, Q is. In some embodiments, Q is selected from the group consisting of:, wherein: R is -CH2CH3, -CH2CH-OCH3, -CH2CHF2, -CH2-CN, CH2(CH3)2-CN, -C(CH3)2-CH2CN, - CH2CH2-CN, cyclohexyl, cyclobutyl, cyclopropyl, pyridin-4-yl, tetrahydropyran-4-yl, tetrahydropyran-4-ylmethyl, oxetan-3-ylmethyl, 2-cyano-5-methoxyphenyl,2-cyano-5-methoxymethylphenyl, 2-cyano-6-(methoxymethyl)phenyl, 2-cyano-6-bromophenyl, 2-methoxyethan-1-yl, 2-cyanopropan-2-yl, 2-tetrahydropyran-4-ylethan-1-yl, 3-cyanopentan-3-yl, 2-cyano-4-methoxybutan-2-yl, or R is, R24is hydrogen, chloro, -CN, -CH3, -CH2CH3, -CHF2, -CF3, -CH2-CN, -CH(CN)-CH3, -C(CH3)2-CN, -C(CH2CH3)2-CN, -C H2-CH2-CN, -C(CH3)=N-O-CH(CH3)2, -C(CH3)=N-O-CH3, -C(O)-N(CH3)2, -C(O)-NH-CH3, -OCH3, -CH2 -O-CH3, -C≡CH, -C≡C-CH3, -S(O)2CH3, 1-(cyclopentyl)-1-cyanoethan-1-yl, 1-(tetrahydropyran-4-yl)-1-cyanoethan-1-yl, 1-(tetrahydrofuran-3-yl)-1-cyanoethan-1-yl, 1,3-dimethoxy-2-cyanopropan-2-yl, 1,4-dimethylpyrazol-5-yl, 1-cyanocyclobutyl, 1-cyanocyclopropyl, 1-cyanocylopentyl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-ylcyanomethyl, 1-methylpiperidin-4-yl, 1-methylpyrazol-5-yl, 1-oxoindolin-5-yl, 1-oxoisoindolin-4-yl, 1-oxoisoindolin-6-yl, 2-(2-methoxyethan-1-yl)phenyl, 2-(methoxymethyl)phenyl, 2-(tetrahydropyran-4-yloxy)phenyl, 2,2-difluoro-benzo[d][1,3]dioxol-4-yl, 2,3-dicyanopropan-2-yl, 2-chlorophenyl, 2-cyano-3-(tetrahydropyran-4-yl)propan-2-yl, 2-cyano-3-chlorophenyl, 2-cyano-3-fluorophenyl, 2-cyano-3-methoxyphenyl, 2-cyano-4-fluorophenyl, 2-cyano-4-chlorophenyl, 2-cyano-5-chlorophenyl, 2-cyano-5-fluorophenyl, 2-cyano-5-methoxyphenyl, 2-cyano-6-chlorophenyl, 2-cyano-6-fluorophenyl, 2-cyano-6-(tetrahydropyran-4-yloxy)phenyl, 2-cyanomethylphenyl, 2-cyanophenyl, 2-cyanopropan-2-yl, 2-cyclopentylphenyl, 2-difluoromethoxyphenyl, 2-fluorophenyl, 2-methoxy-6-cyanophenyl, 2-methoxyphenyl, 2-methoxycarbonylphenyl, 2-nitrophenyl, 2-oxopyrrolidin-1-yl, 2-phenoxyphenyl, 3-(1,1-dioxothiomorpholin-4-ylmethyl)phenyl, 3-(2-methoxyethan-1-yl)phenyl, 3,5-difluoro-4-(pyrrolidin-1-ylcarbonyl)phenyl, 3-cyano-2-methylpropan-2-yl, 3-cyanomethylphenyl, 3-cyanopentan-3-yl , 3-cyanophenyl, 3-hydroxy-2-methylbutan-2-yl, 3-hydroxy-3-methyl-but-1-yne-1-yl, 3-methoxy-2-methylbutan-2-yl, 3-methoxymethyl-5-methylisoxazol-4-yl, 3-methoxyphenyl, 3-methoxycarbonylphenyl, 3-oxo-2-methylbutan-2-yl, 4-cyanophenyl, 4-cyanotetrahydropyran-4-yl, 4-methoxyphenyl, benzo[d][1,3]dioxol-4-yl, benzo[d]oxazol-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, cyclobutyl, cyclopropyl, cyclopropylcyanomethyl, N-methoxycyclopropanecarbimidoyl, phenyl, pyridin-2-ylmethyl, pyridin-3-yl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, tetrahydrofuran-3-ylmethyl, tetrahydrofuran-3-ylcyanomethyl, tetrahydropyran-4-yl, or tetrahydropyran-4-ylcyanomethyl; R27is hydrogen, -CH3, -CHF2, -CH2CH3, -CH2-O-CH3, - CH2CN, -CN, -CH2-O-CH2-CN, -C(O)-N(CH3)2, -C(O)-NH-CH3, -CH2-O-CH2-C≡CH, 2-methoxyphenyl, 3-methoxyphenyl, 2,2-difluorobenzo[d][1,3]dioxol-4-yl, 2-cyanophenyl, 3-cyanophenyl, phenyl, 2- benzyl methyl ether, 2-(2-methoxyethyl) benzene, 2-(2-difluoromethoxyethyl)benzene, 2-(2-dimethylmethoxyethyl)benzene, pyridin-3-yl, pyridin-2-yl, pyridin-3-ylmethyl, or tetrahydropyridin-4-yl, R24and R27are taken together to form 4-cyanobenzene-1,2-diyl, 3-cyanobenzene-1,2-diyl, 5-methyl-5-cyanotetrahydropyran-3,4-diyl, 3-cyanocyclohexan-1,2-diyl, 3-methoxybenzene-1,2-diyl, benzene-1,2-diyl, 3-oxocyclohexyl-1,2-diyl, 3-cyanocyclopentan-1,2-diyl, or pyridin-3,4-diyl; R28is hydrogen, -CH3, or -CH2-O-CH3; and R29is hydrogen, acetyl, CN, -CH2-CN, -CH2-CH2-CN, -CH2-O-CH3, -CH=CH-CN, -CH2-O-C(O)-N(CH3)2, morpholin-4-ylmethyl, pyrazol-1-ylmethyl, pyridin-3-yl, pyridin-3-ylethynyl, pyridin-2-yloxymethyl, or 2-cyanopropan-2-yl, or R28and R29are taken together to form 2,3-dihydrobenzofuran-3,3-diyl, 2,3-dihydrofuro[2,3-b]pyridin-3,3-diyl, tetrahydropyran-3,3-diyl, 6,7-dihydro-5H-cyclopenta[c]pyridin-6-yl, tetrahydropyran-4,4-diyl, or 4-methoxycyclohexane. In some.. In some embodiments, R3is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -CH(CH3)CH2CH3, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxybenzyl, or tetrahydropyran-4-yl.In an aspect, the invention features a compound having the structure of Formula IIa or Formula IIb:, Formula IIa Formula IIb or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9’, or >CR9R9’where the carbon is bound to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R6)- where C is bound to -C(R7R8)-, -C(O)NH-CH(R6)- where C is bound to -C(R7R8)-, optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is a linker; X3is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; each R’is, independently, hydrogen or optionally substituted C1-C4 alkyl; Y1is C, CH, or N; Y2, Y3, Y4, and Y7are, independently, C or N; Y5is CRx, CH, CH2, or N; Y6is CRz, C(O), CH, CH2, or N;Rxis hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; Rzis hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; R13is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R13and R2combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R2is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R14is absent, or R2and R14combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 heteroalkyl, cyclopropyl, or cyclobutyl; R6is hydrogen or methyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6and R7combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7and R8combine with the carbon atom to which they are attached to form C=CR7’R8’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7aand R8aare, independently, hydrogen, halogen, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7’is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10- membered heteroaryl, or optionally substituted 6- to 10-membered aryl, orR7’and R8’combine with the carbon atom to which they are attached to form optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R9and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9’is hydrogen or optionally substituted C1-C6 alkyl; or R9and R9’, combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10is hydrogen, halogen, hydroxy, optionally substituted C1-C3 heteroalkyl, or optionally substituted C1-C3 alkyl; R10ais hydrogen or halogen; R11is hydrogen or optionally substituted C1-C3 alkyl; R21is hydrogen or optionally substituted C1-C3 alkyl; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl. In an aspect, the disclosure features a compound of structural Formula IIa-1:, Formula IIa-1 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene,optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9’, or >CR9R9’where the carbon is bound to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R6)- where C is bound to -C(R7R8)-, -C(O)NH-CH(R6)- where C is bound to -C(R7R8)-, optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is a linker; X1is optionally substituted C1-C2 alkylene, NR, O, or S(O)q; X2is O or NH; X3is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; each R’is, independently, hydrogen or optionally substituted C1-C4 alkyl; Y1is C, CH, or N; Y2, Y3, Y4, and Y7are, independently, C or N; Y5is CRx, CH, CH2, or N; Y6is CRz, C(O), CH, CH2, or N; Rxis hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; Rzis hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; R13is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R13and R2combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R2is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl;R14is absent, or R2and R14combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 heteroalkyl, cyclopropyl, or cyclobutyl; R6is hydrogen or methyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6and R7combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7and R8combine with the carbon atom to which they are attached to form C=CR7’R8’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7aand R8aare, independently, hydrogen, halogen, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7’is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10- membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7’and R8’combine with the carbon atom to which they are attached to form optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R9and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9’is hydrogen or optionally substituted C1-C6 alkyl; or R9and R9’, combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10is hydrogen, halogen, hydroxy, optionally substituted C1-C3 heteroalkyl, or optionally substituted C1-C3 alkyl; R10ais hydrogen or halogen; R11is hydrogen or optionally substituted C1-C3 alkyl; and R21is hydrogen or optionally substituted C1-C3 alkyl.In some embodiments, the disclosure features a compound of structural Formula IIa-2:Formula IIa-2 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9’, or >CR9R9’where the carbon is bound to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R6)- where C is bound to -C(R7R8)-, -C(O)NH-CH(R6)- where C is bound to -C(R7R8)-, optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is a linker; X1is optionally substituted C1-C2 alkylene, NR, O, or S(O)q; X2is O or NH; X3is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; each R’is, independently, hydrogen or optionally substituted C1-C4 alkyl; Y1is C, CH, or N; Y2, Y3, Y4, and Y7are, independently, C or N; Y5is CH, CH2, CF, CHF, CF2 or N; Y6is C(O), CH, CH2, CF, CHF, CF2 or N;R13is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R13and R2combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R2is absent, hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2- C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted C1-C3 acyl; R14is absent, or R2and R14combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 heteroalkyl, cyclopropyl, or cyclobutyl; R6is hydrogen or methyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6and R7combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7and R8combine with the carbon atom to which they are attached to form C=CR7’R8’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7aand R8aare, independently, hydrogen, halogen, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7’is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10- membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7’and R8’combine with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; orR9and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9’is hydrogen or optionally substituted C1-C6 alkyl; or R9and R9’, combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10is hydrogen, halogen, hydroxy, optionally substituted C1-C3 heteroalkyl, or optionally substituted C1-C3 alkyl; R10ais hydrogen or halogen; R11is hydrogen or optionally substituted C1-C3 alkyl; and R21is hydrogen or optionally substituted C1-C3 alkyl. In some embodiments, provided herein is a compound having the structure of Formula IIa-3:Formula IIa-3 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)- where the amino nitrogen is bound to the carbon atom of - CH(R10)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; B is -CH(R9)- or >C=CR9R9’where the carbon is bound to the carbonyl carbon of -N(R11)C(O)- , optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R6)- where C is bound to -C(R7R8)-, -C(O)NH-CH(R6)- where C is bound to -C(R7R8)-, optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or a linker; W is a cross-linking group comprising a vinyl ketone, a vinyl sulfone, an ynone, a haloacetal, or an alkynyl sulfone;X1is optionally substituted C1-C2 alkylene, NR, O, or S(O)q; X2is O or NH; X3is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; each R’is, independently, H or optionally substituted C1-C4 alkyl; Y1is C, CH, or N; Y2, Y3, Y4, and Y7are, independently, C or N; Y5is CH, CH2, CF, CHF, CF2 or N; Y6is C(O), CH, CH2, CF, CHF, CF2 or N; R13is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R13and R2combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R2is absent, hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2- C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted C1-C3 acyl; R14is absent, or R2and R14combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6is hydrogen or methyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6and R7combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7and R8combine with the carbon atom to which they are attached to form C=CR7’R8’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7aand R8aare, independently, hydrogen, halo, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl;R7’is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10- membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7’and R8’combine with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, or R9and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9’is hydrogen or optionally substituted C1-C6 alkyl; R10is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R10ais hydrogen or halo; and R11is hydrogen or C1-C3 alkyl. In some embodiments, the disclosure features a compound of structural Formula IIa-4:Formula IIa-4 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)- where the amino nitrogen is bound to the carbon atom of - CH(R10)-, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bound to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene;G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R6)- where C is bound to -C(R7R8)-, -C(O)NH-CH(R6)- where C is bound to -C(R7R8)-, optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or a linker; W is a cross-linking group comprising a vinyl ketone, a vinyl sulfone, an ynone, a haloacetal, or an alkynyl sulfone; X1is optionally substituted C1-C2 alkylene, NR, O, or S(O)q; X2is O or NH; X3is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; each R’is, independently, H or optionally substituted C1-C4 alkyl; Y1is C, CH, or N; Y2, Y3, Y4, and Y7are, independently, C or N; Y5and Y6are, independently, CH, CF or N; R13is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3-- to 6-membered heterocycloalkyl, optionally substituted 6 to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2is hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted C1-C3 acyl; R14is absent, or R2and R14combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6is hydrogen or methyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6and R7combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, orR7and R8combine with the carbon atom to which they are attached to form C=CR7’R8’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7’is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10- membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7’and R8’combine with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R10is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; and R11is hydrogen or C1-C3 alkyl. In some embodiments of compounds of the present invention, G is optionally substituted C1- C4 heteroalkylene. In some embodiments, a compound having the structure of Formula IIa-5 is provided:Formula IIa-5 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)- where the amino nitrogen is bound to the carbon atom of - CH(R10)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bound to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; L is absent or a linker;W is a cross-linking group comprising a vinyl ketone, a vinyl sulfone, an ynone, or an alkynyl sulfone; X2is O or NH; X3is N or CH; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; each R’is, independently, H or optionally substituted C1-C4 alkyl; Y1is C, CH, or N; Y2, Y3, Y4, and Y7are, independently, C or N; Y5and Y6are, independently, CH, CF or N; R13is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2is hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted C1-C3 acyl; R14is absent, or R2and R14combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6is hydrogen or methyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6and R7combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7and R8combine with the carbon atom to which they are attached to form C=CR7’R8’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7’is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10- membered heteroaryl, or optionally substituted 6- to 10-membered aryl, orR7’and R8’combine with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R10is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; and R11is hydrogen or C1-C3 alkyl. In some embodiments of compounds of the present invention, X2is NH. In some embodiments, X3is CH. In some embodiments, R11is hydrogen. In some embodiments, R11is C1-C3 alkyl. In some embodiments, R11is methyl. In some embodiments, a compound of the present invention has the structure of Formula IIa- 6:Formula IIa-6 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)- where the amino nitrogen is bound to the carbon atom of - CH(R10)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bound to the carbonyl carbon of -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; L is absent or a linker; W is a cross-linking group comprising a vinyl ketone, a vinyl sulfone, an ynone, or an alkynyl sulfone; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; each R’is, independently, H or optionally substituted C1-C4 alkyl; Y1is C, CH, or N; Y2, Y3, Y4, and Y7are, independently, C or N;Y5and Y6are, independently, CH or N; R13is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2is hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R14is absent, or R2and R14combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6is hydrogen or methyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6and R7combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7and R8combine with the carbon atom to which they are attached to form C=CR7’R8’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7’is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10- membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7’and R8’combine with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; and R10is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl. In some embodiments of a compound of the present invention, X1is optionally substituted C1- C2 alkylene. In some embodiments, X1is methylene. In some embodiments, X1is methylene substituted with a C1-C6 alkyl group or a halogen. In some embodiments, X1is -CH(Br)-. In someembodiments, X1is -CH(CH3)-. In some embodiments, R5is hydrogen. In some embodiments, R5is C1-C4 alkyl optionally substituted with halogen. In some embodiments, R5is methyl. In some embodiments, Y4is C. In some embodiments, R4is hydrogen. In some embodiments, Y5is CH. In some embodiments, Y5is CF. In some embodiments, Y6is CH. In some embodiments, Y6is CF. In some embodiments, Y1is C. In some embodiments, Y2is C. In some embodiments, Y3is N. In some embodiments, R3is absent. In some embodiments, Y7is C. In some embodiments, Y4is C and R15is F. In some embodiments, a compound of the present invention has the structure of Formula IIa- 7:Formula IIa-7 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is -N(H or CH3)C(O)-(CH2)- where the amino nitrogen is bound to the carbon atom of -CH(R10)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bound to the carbonyl carbon of -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; L is absent or a linker; W is a cross-linking group comprising a vinyl ketone, a vinyl sulfone, an ynone, or an alkynyl sulfone; R13is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl;R14is absent, or R2and R14combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6is hydrogen or methyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6and R7combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7and R8combine with the carbon atom to which they are attached to form C=CR7’R8’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7’is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10- membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7’and R8’combine with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; and R10is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl. In some embodiments of a compound of the present invention, R6is hydrogen. In some embodiments, R2is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6- membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R2is optionally substituted C1-C6 alkyl. In some embodiments, R2 is fluoroalkyl. In some embodiments, R2is ethyl. In some embodiments, R2 is -CH2CF3. In some embodiments, R2 is C2-C6 alkynyl. In some embodiments, R2 is -CHC≡CH. In some embodiments, R2 is -CH2C≡CCH3. In some embodiments, R7is optionally substituted C1-C3 alkyl. In some embodiments, R7is C1-C3 alkyl. In some embodiments, R8is optionally substituted C1-C3 alkyl. In some embodiments, R8is C1-C3 alkyl.In some embodiments, a compound of the present invention has the structure of Formula IIa-Formula IIa-8 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is -N(H or CH3)C(O)-(CH2)- where the amino nitrogen is bound to the carbon atom of -CH(R10)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bound to the carbonyl carbon of -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; L is absent or a linker; W is a cross-linking group comprising a vinyl ketone, a vinyl sulfone, an ynone, or an alkynyl sulfone; R13is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2is C1-C6 alkyl or 3 to 6-membered cycloalkyl; R7is C1-C3 alkyl; R8is C1-C3 alkyl; and R9is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl. In some embodiments of a compound of the present invention, R13is optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 6-membered cycloalkenyl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R13is optionally substituted 6-membered aryl, optionally substituted 6-membered cycloalkenyl, or optionally substituted 6-membered heteroaryl.In some embodiments of a compound of the present invention,,,stereoisomer (e.g., atropisomer) thereof. In some embodiments of a compound of the present invention,stereoisomer (e.g., atropisomer) thereof. In some embodiments of a compound of the present invention,stereoisomer thereof. In some embodiments,.In some embodiments, a compound of the present invention has the structure of Formula IIa- 9:Formula IIa-9 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is -N(H or CH3)C(O)-(CH2)- where the amino nitrogen is bound to the carbon atom of -CH(R10)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bound to the carbonyl carbon of -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; L is absent or a linker; W is a cross-linking group comprising a vinyl ketone, a vinyl sulfone, an ynone, or an alkynyl sulfone; R2is C1-C6 alkyl, C1-C6 fluoroalkyl, or 3- to 6-membered cycloalkyl; R7is C1-C3 alkyl; R8is C1-C3 alkyl; and R9is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl Xeand Xfare, independently, N, CH or CR17; and R12is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 6-membered heterocycloalkylene. R17is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments of a compound of the present invention, Xeis N and Xfis CH. In some embodiments, Xeis CH and Xfis N.In some embodiments of compounds of the present invention, R12is optionally substituted C1- C6 heteroalkyl. In some embodiments, R12is, , , ,. In some embodiments of a compound of the present invention, R12is optionally substituted C1-C6 heteroalkyl. In some embodiments, R12is. In some embodiments, a compound of the present invention has the structure of Formula IIa- 10:Formula IIa-10 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bound to the carbonyl carbon of -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; L is absent or a linker; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; R2is C1-C6 alkyl or 3- to 6-membered cycloalkyl; R7is C1-C3 alkyl; R8is C1-C3 alkyl; R9is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; Xeis CH, or CR17; andR17is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, a compound of the present invention has the structure of Formula IIa-Formula IIa-11 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bound to the carbonyl carbon of -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; L is absent or a linker; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; R2is C1-C6 alkyl or 3- to 6-membered cycloalkyl; R7is C1-C3 alkyl; R8is C1-C3 alkyl; and R9is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl.In some embodiments, a compound of the present invention has the structure of Formula II- VI:Formula II-VI or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)- where the amino nitrogen is bound to the carbon atom of - CH(R10)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene (e.g., phenyl or phenol), or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9’, or >CR9R9’where the carbon is bound to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6- membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R6)- where C is bound to -C(R7R8)-, -C(O)NH-CH(R6)- where C is bound to -C(R7R8)-, optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or a linker; W is a cross-linking group comprising a vinyl ketone, a vinyl sulfone, an ynone, a haloacetal, or an alkynyl sulfone; X1is optionally substituted C1-C2 alkylene, NR, O, or S(O)q; X2is O or NH; X3is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2;each R’is, independently, H or optionally substituted C1-C4 alkyl; Y1is C, CH, or N; Y2, Y3, Y4, and Y7are, independently, C or N; Y5is CH, CH2, CF, CHF, CF2 or N; Y6is C(O), CH, CH2, CF, CHF, CF2 or N; R2is absent, hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2- C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted C1-C3 acyl; R14is absent, or R2and R14combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6is hydrogen or methyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6and R7combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7and R8combine with the carbon atom to which they are attached to form C=CR7’R8’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7aand R8aare, independently, hydrogen, halo, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7’is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10- membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7’and R8’combine with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R9and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;R9’is hydrogen or optionally substituted C1-C6 alkyl; or R9and R9’, combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R10ais hydrogen or halo; R11is hydrogen or C1-C3 alkyl; R21is hydrogen or C1-C3 alkyl (e.g., methyl); and Xeand Xfare, independently, N or CH. In some embodiments, a compound of the present invention has the structure of Formula II- VIa:Formula II-VIa or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene (e.g., phenyl or phenol), or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bound to the carbonyl carbon of -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; L is absent or a linker; W is a cross-linking group comprising a vinyl ketone, a vinyl sulfone, an ynone, or an alkynyl sulfone; X1is optionally substituted C1-C2 alkylene, NR, O, or S(O)q; X2is O or NH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; each R’is, independently, H or optionally substituted C1-C4 alkyl; R2is C1-C6 alkyl, C1-C6 fluoroalkyl, or 3- to 6-membered cycloalkyl; R7is C1-C3 alkyl;R8is C1-C3 alkyl; and R9is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; Xeand Xfare, independently, N or CH; R11is hydrogen or C1-C3 alkyl; and R21is hydrogen or C1-C3 alkyl. In some embodiments of a compound of the present invention, Xeis N and Xfis CH. In some embodiments, Xeis CH and Xfis N. In some embodiments, a compound of the present invention has the structure of Formula II- VIb:Formula II-VIb or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene (e.g., phenyl or phenol), or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9)- where the carbon is bound to the carbonyl carbon of -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; R9is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; L is absent or a linker; and W is a cross-linking group comprising a vinyl ketone, a vinyl sulfone, an ynone, or an alkynyl sulfone. In some embodiments of a compound of the present invention, A is optionally substituted 6- membered arylene.In some embodiments, a compound of the present invention has the structure of Formula II- VIc:Formula II-VIc or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)- where the amino nitrogen is bound to the carbon atom of - CH(R10)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene (e.g., phenyl or phenol), or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9’, or >CR9R9’where the carbon is bound to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6- membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R6)- where C is bound to -C(R7R8)-, -C(O)NH-CH(R6)- where C is bound to -C(R7R8)-, optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or a linker; W is a cross-linking group comprising a vinyl ketone, a vinyl sulfone, an ynone, a haloacetal, or an alkynyl sulfone; X1is optionally substituted C1-C2 alkylene, NR, O, or S(O)q; X2is O or NH; X3is N or CH; q is 0, 1, or 2;R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; each R’is, independently, H or optionally substituted C1-C4 alkyl; Y1is C, CH, or N; Y2, Y3, Y4, and Y7are, independently, C or N; Y5is CH, CH2, CF, CHF, CF2 or N; Y6is C(O), CH, CH2, CF, CHF, CF2 or N; R2is absent, hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2- C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted C1-C3 acyl; R14is absent, or R2and R14combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6is hydrogen or methyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6and R7combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7and R8combine with the carbon atom to which they are attached to form C=CR7’R8’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7aand R8aare, independently, hydrogen, halo, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7’is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10- membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7’and R8’combine with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; orR9and L combine with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocycloalkyl; R9’is hydrogen or optionally substituted C1-C6 alkyl; or R9and R9’, combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R10ais hydrogen or halo; R11is hydrogen or C1-C3 alkyl; and R21is hydrogen or C1-C3 alkyl (e.g., methyl). In some embodiments, Z is -C(O)-. In some embodiments, A is optionally substituted C2-C4 alkylene. In some embodiments, A is optionally substituted C3 alkylene. In some embodiments, A is:. In some embodiments, A is optionally substituted C2-C4 alkenylene. In some embodiments, A is optionally substituted C3 alkenylene. In some embodiments, A is optionally substituted C1-C4 heteroalkylene. In some embodiments, A is optionally substituted C2 heteroalkylene. In some embodiments, A is:. In some embodiments, A has the structure:wherein R13is hydrogen, halo, hydroxy, amino, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; and R13ais hydrogen or halogen. In some embodiments, R13is hydrogen. In some embodiments, R13and R13aare each hydrogen. In some embodiments, R13is hydroxy, methyl, fluoro, or difluoromethyl. In some embodiments, A is an optionally substituted 5- to 10-membered heteroarylene. In some embodiments, A is:. In some embodiments, A is optionally substituted 5- to 6-membered heteroarylene. In some embodiments, A is:,In some embodiments, A is optionally substituted C1-C4 heteroalkylene. In someIn some embodiments, R9is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1- C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7- membered heterocycloalkyl. In some embodiments, R9is:, , , ,,some embodiments, R9is:. In some embodiments, R9is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl. In some embodiments of a compound of the present invention, B is optionally substituted 6- membered arylene. In some embodiments, B is 6-membered arylene. In some embodiments, B is: I, , . In some embodiments,, wherein Z1is N or CH; m is 1 or 2; R18, R19, R20, and R25are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6- membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R18and R20combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R20and R25combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R19and R20combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl.In some embodiments, R13is . In some embodiments, R13is . In some embodiments, R18is methyl. In some embodiments,. In some embodiments of a compound of the present invention, R7is methyl. In some embodiments of a compound of the present invention, R8is methyl. In some embodiments, R21is hydrogen. In some embodiments of a compound of the present invention, B is -CHR9-. In some embodiments, R9is optionally substituted C1-C6 alkyl or optionally substituted 3- to 6-membered cycloalkyl. In some embodiments, B is optionally substituted 6-membered arylene. In some embodiments, B is absent. In some embodiments, L has the structure of Formula L0: Formula L0 wherein X12is O, S, SO2, NH, CH2, C1-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenylene, or optionally substituted C2-C4 alkynylene, and is attached to ring A; and E is a bond, optionally substituted C1-C6alkylene, optionally substituted C1-C6heteroalkylene, optionally substituted C2-C6 alkenylene, optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 8-membered heterocycloalkylene, optionally substituted 5- to 12- membered arylene, or an optionally substituted 5- to 12-membered heteroarylene. In some embodiments of a compound of the present invention, the linker is the structure of Formula II-II: A1-(B1)f-(C1)g-(B2)h-(D1)-(B3)i-(C2)j-(B4)k–A2Formula II-II where A1is a bond between the linker and B; A2is a bond between A and the linker; B1, B2, B3, and B4each, independently, is selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NRN; RNis hydrogen, optionally substituted C1–4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionallysubstituted C1-C7 heteroalkyl; C1and C2are each, independently, selected from carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; f, g, h, i, j, and k are each, independently, 0 or 1; and D1is optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted 3- to 14-membered heterocycloalkylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 6- to 10-membered arylene, optionally substituted C2-C10 polyethylene glycolene, or optionally substituted C1-C10 heteroalkylene, or a chemical bond linking A1-(B1)f-(C1)g- (B2)h- to -(B3)i-(C2)j-(B4)k–A2. In some embodiments, the linker is acyclic. In some embodiments, linker has the structure of Formula II-IIa:Formula II-IIa wherein Xais absent or N; R14is absent, hydrogen or optionally substituted C1-C6 alkyl; and L2is absent, -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene, wherein at least one of Xa, R14, or L2is present. In some embodiments, the linker has the structure:In some embodiments, the linker is or comprises a cyclic moiety. In some embodiments, the linker has the structure of Formula II-IIb:Formula II-IIb wherein o is 0 or 1; R15is hydrogen or optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene; X4is absent, optionally substituted C1-C4alkylene, O, NCH3, or optionally substituted C1-C4heteroalkylene; Cy is optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 8- membered heterocycloalkylene, optionally substituted 6- to 10-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; and L3is absent, -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene. In some embodiments, the linker has the structure of Formula II-IIb-1:Formula II-IIb-1 wherein o is 0 or 1; R15is hydrogen or optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene; Cy is optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 8- membered heterocycloalkylene, optionally substituted 6- to 10-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; and L3is absent, -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene. In some embodiments, the linker has the structure:,,. In some embodiments, the linker has the structure of Formula II-IIc:Formula II-IIc wherein R15is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8- membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene; andR15a, R15b, R15c, R15d, R15e, R15f, and R15gare, independently, hydrogen, halo, hydroxy, cyano, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or , or R15band R15dcombine with the carbons to which they are attached to form an optionally substituted 3- to 8- membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene. In some embodiments, the linker has the structure:In some embodiments, the linker has the structure:,In some embodiments, the linker has the structure. In some embodiments, the linker has the structure. In some embodiments, a linker of Formula II is selected from the group consisting ofIn an aspect, the invention features a compound having the structure of Formula IIIa or Formula IIIb:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene;, , or ; L is a linker; R13is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl;R10is hydrogen, hydroxy, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7and R8are each, independently, selected from F or CH3, or R7and R8combine with the atoms to which they are attached to make a 3-membered cycloalkyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; t is 0, 1, 2, or 3; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl. In an aspect, the invention features a compound having the structure of Formula IIIa-1: ,or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene;, , or ; L is a linker; X4and X5are each, independently, CH2, CH(CH3) or NH; R13is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R10is hydrogen, hydroxy, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7and R8are each, independently, selected from F or CH3, or R7and R8combine with the atoms to which they are attached to make a 3-membered cycloalkyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3. In some embodiments, the disclosure features a compound of structural Formula IIIa-2:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene;, , or ; L is a linker; X4and X5are each, independently, CH2, CH(CH3) or NH; R13is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R10is hydrogen, hydroxy, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; and R7and R8are each, independently, selected from F or CH3, or R7and R8combine with the atoms to which they are attached to make a 3-membered cycloalkyl.In some embodiments, the compound has the structure of Formula IIIa-3:Formula IIIa-3 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene;R13is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R10is hydrogen or optionally substituted C1-C6 heteroalkyl. In some embodiments, R10is hydrogen. In some embodiments, R13is optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R13is optionally substituted phenyl or optionally substituted pyridine. In some embodiments, A is optionally substituted thiazole, optionally substituted triazole, optionally substituted morpholino, optionally substituted piperidinyl, optionally substituted pyridine, or optionally substituted phenyl. In some embodiments, A is optionally substituted thiazole, optionally substituted triazole, optionally substituted morpholino, or phenyl. In some embodiments, A is not an optionally substituted phenyl or benzimidazole. In some embodiments, A is not hydroxyphenyl. In some embodiments, Y8is -NHC(O)- or -NHC(O)NH-. In some embodiments, the compound has the structure of Formula IIIa-4:Formula IIIa-4, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein a is 0 or 1. In some embodiments, the compound has the structure of Formula IIIa-5:Formula IIIa-5, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X2is N or CH; each R3is independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6- membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; and n is an integer from 1 to 4.In some embodiments, the compound has the structure of Formula IIIa-6:, Formula IIIa-6 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula IIIa-7:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein R4and R5are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, the compound has the structure of Formula IIIa-8: ,or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.In some embodiments, the compound has the structure of Formula IIIa-9:Formula IIIa-9, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X3is N or CH; m is 1 or 2; R6, R7, R8, and R11are each independently selected from hydrogen, optionally substituted C1- C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10- membered heteroaryl; or R6and R7combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R7and R8combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R7and R11combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, X3is N. In some embodiments, m is 1. In some embodiments, R11is H. In some embodiments, X3is N, m is 1, and R11is H. In some embodiments, the compound has the structure of Formula IIIa-10: ,or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula IIIa-11: ,or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments (e.g., of any one of Formulae IIIa-10 or IIIa-11), R6is methyl. In some embodiments, the compound has the structure of Formula IIIa-12 or Formula IIIa-13: ,or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula IIIa-a:Formula IIIa-a,or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein a is 0 or 1. In some embodiments, the compound has the structure of Formula IIIa-a1:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X2is N or CH; each R3is independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6- membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; and n is an integer from 1 to 4. In some embodiments, the compound has the structure of Formula IIIa-a2: ,or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.In some embodiments, the compound has the structure of Formula IIIa-a3:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein R4and R5are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, the compound has the structure of Formula IIIa-a4: ,or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula IIIa-a5:Formula IIIa-a5,or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X3is N or CH; m is 1 or 2; R6, R7, R8, and R11are each independently selected from hydrogen, optionally substituted C1- C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10- membered heteroaryl; or R6and R7combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R7and R8combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R7and R11combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, X3is N. In some embodiments, m is 1. In some embodiments, R11is hydrogen. In some embodiments, X3is N, m is 1, and R11is H. In some embodiments, the compound has the structure of Formula IIIa-a6: ,or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula IIIa-a7: ,or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.In some embodiments (e.g., of any one of Formulae IIIa-a6 or IIIa-a7), R6is methyl. In some embodiments, the compound has the structure of Formula IIIa-a8 or Formula IIIa-a9:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula III-IVa:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein a is 0 or 1. In some embodiments, the compound has the structure of Formula III-IVa-1:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X2is N or CH;each R3is independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3 to 6- membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; and n is an integer from 1 to 4. In some embodiments, the compound has the structure of Formula III-IVa-2:Formula III-IVa-2 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula III-Iva-3:Formula III-IVa-3, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein R4and R5are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl.In some embodiments, the compound has the structure of Formula III-IVa-4:Formula III-IVa-4 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula III-IVa-5:Formula III-IVa-5, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X3is N or CH; m is 1 or 2; R6, R7, R8, and R11are each independently selected from hydrogen, optionally substituted C1- C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10- membered heteroaryl; or R6and R7combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R7and R8combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl ; or R7and R11combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, X3is N. In some embodiments, m is 1. In some embodiments, R11is hydrogen. In some embodiments, X3is N, m is 1, and R11is H.In some embodiments, the compound has the structure of Formula III-IVa-6:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula III-IVa-7:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments (e.g., of any one of Formulae III-IVa-6 or III-IVa-7), R6is methyl.In some embodiments, the compound has the structure of Formula III-IVa-8 or Formula III- IVa-9:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, Y8is -NHS(O)2- or -NHS(O)2NH-. In some embodiments, the compound has the structure of Formula III-Va:Formula III-Va, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein a is 0 or 1. In some embodiments, the compound has the structure of Formula III-Va-1:Formula III-Va-1, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X2is N or CH;each R3is independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6- membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; and n is an integer from 1 to 4. In some embodiments, the compound has the structure of Formula III-Va-2:Formula III-Va-2 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula III-Va-3:Formula III-Va-3, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein R4and R5are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl.In some embodiments, the compound has the structure of Formula III-Va-4:Formula III-Va-4 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula III-Va-5:Formula III-Va-5, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X3is N or CH; m is 1 or 2; R6, R7, R8, and R11are each independently selected from hydrogen, optionally substituted C1- C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10- membered heteroaryl; or R6and R7combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R7and R8combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R7and R11combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, X3is N. In some embodiments, m is 1. In some embodiments, R11is hydrogen. In some embodiments, X3is N, m is 1, and R11is H.In some embodiments, the compound has the structure of Formula III-VIa:Formula III-VIa, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein a is 0 or 1. In some embodiments, the compound has the structure of Formula III-VIa-1:Formula III-VIa-1, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X2is N or CH; each R3is independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6- membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; and n is an integer from 1 to 4. In some embodiments, the compound has the structure of Formula III-VIa-2:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula III-VIa-3:Formula III-Via-3, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein R4and R5are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, the compound has the structure of Formula III-Via-4:Formula III-Via-4 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.In some embodiments, the compound has the structure of Formula III-VIa-5:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X3is N or CH; m is 1 or 2; R6, R7, R8, and R11are each independently selected from hydrogen, optionally substituted C1- C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10- membered heteroaryl; or R6and R7combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R7and R8combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R7and R11combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, X3is N. In some embodiments, m is 1. In some embodiments, R11is hydrogen. In some embodiments, X3is N, m is 1, and R11is H. In some embodiments, the compound has the structure of Formula III-VIIa:Formula III-VIIa, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein R9is H or C1-C6 alkyl; and a is 0 or 1.In some embodiments, the compound has the structure of Formula III-VIIa-1:Formula III-VIIa-1, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X2is N or CH; each R3is independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6- membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; and n is an integer from 1 to 4. In some embodiments, the compound has the structure of Formula III-VIIa-2:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula III-VIIa-3:Formula III-VIIa-3,or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein R4and R5are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, the compound has the structure of Formula III-VIIa-4:Formula III-VIIa-4 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula III-VIIa-5:Formula III-VIIa-5, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X3is N or CH; m is 1 or 2; R6, R7, R8, and R11are each independently selected from hydrogen, optionally substituted C1- C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10- membered heteroaryl; or R6and R7combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; orR7and R8combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R7and R11combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, X3is N. In some embodiments, m is 1. In some embodiments, R11is hydrogen. In some embodiments, X3is N, m is 1, and R11is H. In some embodiments (e.g., of any one of Formulae VIIa, VIIa-1, VIIa-2, VIIa-3, VIIa-4, or VIIa-5), R9is methyl. In some embodiments, Y is -NHS(O)- or -NHS(O)NH-. In some embodiments, the compound has the structure of Formula III-VIIIa:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein a is 0 or 1. In some embodiments, the compound has the structure of Formula III-VIIIa-1:Formula III-VIIIa-1, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X2is N or CH; each R3is independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6- membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; and n is an integer from 1 to 4.In some embodiments, the compound has the structure of Formula III-VIIIa-2:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula III-VIIIa-3:Formula III-VIIIa-3, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein R4and R5are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, the compound has the structure of Formula III-VIIIa-4:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula III-VIIIa-5:Formula III-VIIIa-5, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X3is N or CH; m is 1 or 2; R6, R7, R8, and R11are each independently selected from hydrogen, optionally substituted C1- C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10- membered heteroaryl; or R6and R7combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R7and R8combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R7and R11combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, X3is N. In some embodiments, m is 1. In some embodiments, R11is hydrogen. In some embodiments, X3is N, m is 1, and R11is H. In some embodiments, the compound has the structure of Formula III-IXa:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein a is 0 or 1. In some embodiments, the compound has the structure of Formula III-IXa-1:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X2is N or CH; each R3is independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6- membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; and n is an integer from 1 to 4. In some embodiments, the compound has the structure of Formula III-IXa-2:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula III-IXa-3:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein R4and R5are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, the compound has the structure of Formula III-IXa-4:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula III-IXa-5:Formula III-IXa-5, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X3is N or CH; m is 1 or 2; R6, R7, R8, and R11are each independently selected from hydrogen, optionally substituted C1- C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10- membered heteroaryl; or R6and R7combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; orR7and R8combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R7and R11combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, X3is N. In some embodiments, m is 1. In some embodiments, R11is hydrogen. In some embodiments, X3is N, m is 1, and R11is H. In some embodiments, the compound has the structure of Formula III-Xa:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein a is 0 or 1. In some embodiments, the compound has the structure of Formula III-Xa-1:Formula III-Xa-1, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X2is N or CH; each R3is independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6- membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; and n is an integer from 1 to 4.In some embodiments, the compound has the structure of Formula III-Xa-2:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, the compound has the structure of Formula III-Xa-3:Formula III-Xa-3, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein R4and R5are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 11-membered heterocycloalkyl (e.g., optionally substituted 3- to 6-membered heterocycloalkyl), optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, the compound has the structure of Formula III-Xa-4:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.In some embodiments, the compound has the structure of Formula III-Xa-5:Formula III-Xa-5, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X3is N or CH; m is 1 or 2; R6, R7, R8, and R11are each independently selected from hydrogen, optionally substituted C1- C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10- membered heteroaryl; or R6and R7combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R7and R8combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R7and R11combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, X3is N. In some embodiments, m is 1. In some embodiments, R11is hydrogen. In some embodiments, X3is N, m is 1, and R11is H. In some embodiments of any aspect described herein, a is 0. In some embodiments of any of the above, a is 0. In some embodiments of any aspect described herein, R2is optionally substituted C1-C6 alkyl. In some embodiments, R2is selected from -CH2CH3 or -CH2CF3.In an aspect, the invention features a compound having the structure of Formula IVa or Formula IVb:, Formula IVa Formula IVb or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl; R2is optionally substituted C1-C6alkyl; R3is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; andt is 0, 1, 2, or 3. In some embodiments, the compound has the structure of Formula IVa-1 or Formula IVb-1:, Formula IVa-1 Formula IVb-1 or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl; R2is optionally substituted C1-C6alkyl; R3is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl.In some embodiments, the compound has the structure of Formula IVa-2:, Formula IVa-2 or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl; R2is optionally substituted C1-C6 alkyl; R3is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3. In some embodiments, the disclosure features a compound of structural Formula IVa-3: ,or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl; R2is optionally substituted C1-C6 alkyl; and R3is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl. In some embodiments, provided herein is a compound having the structure of Formula IVa-4:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments of compounds of the present invention, A is optionally substituted thiazole, optionally substituted oxazole, optionally substituted morpholino, optionally substituted pyrrolidinyl, optionally substituted pyridyl, optionally substituted azetidinyl, optionally substituted pyrazinyl, optionally substituted pyrimidine, optionally substituted piperidinyl, optionally substituted oxadiazole, optionally substituted thiadiazole, optionally substituted triazole, optionally substituted thiomorpholino, or optionally substituted phenyl. In some embodiments, the disclosure features a compound of structural Formula IVa5:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.In some embodiments, a compound having the structure of Formula IVa6 is provided:Formula IVa6, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein R4, R5, and R6are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; or R4and R5combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R4and R6combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl. In some embodiments, a compound of the present invention has the structure of Formula IVa7:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.In some embodiments, a compound of the present invention has the structure of Formula IVa8:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, a compound of the present invention has the structure of Formula IVa9f:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments of a compound of the present invention, R2is:. In some embodiments of a compound of the present invention, R3is optionally substituted C1- C6 alkyl. In some embodiments, R3is:.In some embodiments of a compound of the present invention, R3is optionally substituted C1- C3 heteroalkyl. In some embodiments, R3is:. In some embodiments of a compound of the present invention, A is optionally substituted 5- toIn some embodiments of a compound of the present invention, A is optionally substituted phenyl. In some embodiments, A is:In some embodiments of a compound of the present invention, A is optionally substituted 3- to 6-membered heterocycloalkylene. In some embodiments, A is selected from the following, or a stereoisomer thereof:In some embodiments of a compound of the present invention, the linker is the structure of Formula IV-III: A1-(B1)f-(C1)g-(B2)h-(D1)-(B3)i-(C2)j-(B4)k–A2Formula IV-III, wherein A1is a bond between the linker and CH(R3); A2is a bond between A and the linker; B1, B2, B3, and B4each, independently, is selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NRN; each RNis, independently, hydrogen, optionally substituted C1–C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted C1-C7 heteroalkyl; C1and C2are each, independently, selected from carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; f, g, h, i, j, and k are each, independently, 0 or 1; and D1is optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted 3- to 14-membered heterocycloalkylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 6- to 10-membered arylene, optionally substituted C2-C10 polyethylene glycolene, or optionally substituted C1-C10 heteroalkylene, or a chemical bond linking A1-(B1)f-(C1)g-(B2)h- to -(B3)i-(C2)j-(B4)k–A2. In some embodiments of a compound of the present invention, the linker is or comprises a cyclic moiety. In some embodiments, the linker has the structure of Formula IV-IIIa:Formula IV-IIIa, wherein o is 0 or 1; R7is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene; X1is absent, optionally substituted C1-C4alkylene, O, NCH3, or optionally substituted C1-C4heteroalkylene; Cy is optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 12- membered heterocycloalkylene, optionally substituted 6- to 10-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; and L2is absent, -SO2-, -NH-, optionally substituted C1-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted 3- to 6-membered heterocycloalkylene. In some embodiments, the linker is selected from, or a stereoisomer thereof:. In some embodiments, the linker is selected from, or a stereoisomer thereof:In some embodiments, a compound of the present invention has the structure of Formula IVa9:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein Cy1is optionally substituted spirocyclic 8- to 11-membered heterocycloalkylene or optionally substituted bicyclic 7- to 9-membered heterocycloalkylene; and wherein W comprises a vinyl ketone or a vinyl sulfone. In some embodiments, Cy1is optionally substituted spirocyclic 10- to 11-membered heterocycloalkylene. In some embodiments, a compound of the present invention has the structure of Formula IVa10:Formula IVa10, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X2is O, C(R11)2, NR12, S, or SO2; r is 1 or 2; each t is, independently, 0, 1, or 2; R11and R12are each, independently, hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 heteroalkyl, or optionally substituted 3- to 5-membered cycloalkyl; and each R13is, independently, -CH3.In some embodiments, a compound of the present invention has the structure of Formula IVa11:Formula IVa11, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X2is O, C(R11)2, NR12, S, or SO2; r is 1 or 2; each t is, independently, 0, 1, or 2; R11and R12are each, independently, hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 heteroalkyl, optionally substituted 3- to 6- membered heterocycloalkyl, or optionally substituted 3- to 5-membered cycloalkyl; and each R13is, independently, -CH3, F, or two R13attached to the same atom combine with the atom to which they are attached to form an optionally substituted C3-C6 cycloalkyl, or two R13attached to the same atom combine with the atom to which they are attached to form an optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, a compound of the present invention has the structure of Formula IVa12:Formula IVa12 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.In some embodiments, a compound of the present invention has the structure of Formula IVa13:Formula IVa13 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, a compound of the present invention has the structure of Formula IVa14:Formula IVa14 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, X2is O. In some embodiments, X2is S. In some embodiments, X2is SO2. In some embodiments, X2is NR12. In some embodiments, R12is selected from, or a stereoisomer thereof:In some embodiments, X2is C(R11)2. In some embodiments, each R11is hydrogen.In some embodiments, a compound of the present invention has the structure of Formula IVa15:Formula IVa15, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein Q1is CH2, NRN, or O; Q2is CO, NRN, or O; and Z is optionally substituted 3- to 6-membered heterocycloalkylene or optionally substituted 5- to 10-membered heteroarylene; or wherein Q1-Q2-Z is an optionally substituted 9- to 10-membered spirocyclic heterocycloalkylene. In some embodiments, a compound of the present invention has the structure of Formula IVa16:Formula IVa16, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein R14is fluoro, hydrogen, or C1-C3 alkyl; and u is 0 or 1. In some embodiments, R14is fluoro and u is 1. In some embodiments, R14is hydrogen and u is 0.In some embodiments, a compound of the present invention has the structure of Formula IVa17:Formula IVa17 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, a compound of the present invention has the structure of Formula IVa18:Formula IVa18 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.In an aspect, the disclosure features a compound of structural Formula VIa-1:Formula VIa-1 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; W is a cross-linking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, an N-ethoxycarbonyl-2- ethoxy-1,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium, or a glycal; X6is CH2 or O; m is 1 or 2; n is 0 or 1; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl; and R2is optionally substituted C1-C6 alkyl.In an aspect, the invention features a compound having the structure of Formula Va or Formula Vb:, Formula Va Formula Vb or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; R1is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl; R2is optionally substituted C1-C6 alkyl; R3is optionally substituted C1-C6alkyl or optionally substituted C1-C3heteroalkyl; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3.In some embodiments, the compound has the structure of Formula Va-1:, Formula Va-1 or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl; R2is optionally substituted C1-C6 alkyl; R3is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3. In some embodiments, the compound has the structure of Formula Va-2:, Formula Va-2 or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl;R2is optionally substituted C1-C6 alkyl; and R3is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl. In some embodiments, a compound of the present invention has the structure of Formula V- Ia:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof. In some embodiments, a compound of the present invention has the structure of Formula V-II- 1:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.In some embodiments, a compound of the present invention has the structure of Formula V-II- 2:Formula V-II-2, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein R6, R7, and R8are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocycloalkyl; or R6and R7combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; or R6and R8combine with the atoms to which they are attached to form an optionally substituted 3- to 8- membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl. In some embodiments, a compound of the present invention has the structure of Formula V-II- 3:Formula V-II-3 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof.In some embodiments, a compound of the present invention has the structure of Formula V-II-or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein X2is CH2 or O; and o is 1 or 2. In some embodiments, the compound has the structure of Formula VIa or Formula VIb:or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; W is a cross-linking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, an N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium, or a glycal; X6is CH2 or O; m is 1 or 2; n is 0 or 1; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl; R2is optionally substituted C1-C6 alkyl; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3. In some embodiments, the compound has the structure of Formula VIa-1:, Formula VIa-1 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; W is a cross-linking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, an N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium, or a glycal; X6is CH2 or O; m is 1 or 2; n is 0 or 1; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl; R2is optionally substituted C1-C6 alkyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3. In some embodiments, the compound has the structure of Formula VIa-2:, Formula VIa-2 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; W is a cross-linking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, an N-ethoxycarbonyl-2- ethoxy-1,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium, or a glycal; X6is CH2 or O; m is 1 or 2; n is 0 or 1; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl; andR2is optionally substituted C1-C6 alkyl. In some embodiments of a compound of the present invention, X2is CH2. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments of a compound of the present invention, X6is O. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments of a compound of the present invention, R2is:. In some embodiments of a compound of the present invention, R3is optionally substituted C1- C6 alkyl. In some embodiments, R3is:. In some embodiments of a compound of the present invention, R3is or optionally substituted 3- to 6-membered cycloalkyl. In some embodiments, R3is:. In some embodiments of a compound of the present invention, A is optionally substituted 5- to 10-membered heteroarylene. In some embodiments, A is:. In some embodiments of a compound of the present invention, A is optionally substituted phenyl. In some embodiments, A is:In some embodiments of a compound of the present invention, A is optionally substituted 3- to 6-membered heterocycloalkylene. In some embodiments, A is selected from the following, or a stereoisomer thereof:, , . In some embodiments of a compound of the present invention, m is 1. In some embodiments, n is 1. In some embodiments, X1is CH2. In some embodiments, X6is O. In some embodiments, m is 1, n is 1, and X6is CH2. In some embodiments, m is 1, n is 1, and X6is O. In some embodiments of a compound of the present invention, m is 2. In some embodiments, X6is CH2. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, m is 2, X6is CH2, and n is 1. In some embodiments, m is 2 and X6is O. In some embodiments, m is 2, X6is O, and n is 1. In some embodiments, m is 2, X6is O, and n is 0. In some embodiments of a compound of the present invention, W comprises an aziridine. In some embodiments, W comprises an optionally substituted cyclopropyl-aziridinyl moiety. In some embodiments, W is selected from the following, or a stereoisomer thereof:In some embodiments of a compound of the present invention, W comprises an epoxide. In some embodiments, W is selected from the following, or a stereoisomer thereof:, ,. In an aspect, the invention features a compound having the structure of Formula VIIa or Formula VIIb:, Formula VIIa Formula VIIb or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; X6, X7, and X8are each independently selected from CH2, CHF, CF2, C=O, or O; m is 1 or 2; n is 0 or 1; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl; R2is optionally substituted C1-C6alkyl; R3is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl,and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3. In some embodiments, the compound has the structure of Formula VIIa-1:, Formula VIIa-1 or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; X6, X7, and X8are each independently selected from CH2, CHF, CF2, C=O, or O; m is 1 or 2; n is 0 or 1; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl; R2is optionally substituted C1-C6 alkyl; R3is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium;each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3. In some embodiments, the disclosure features a compound of structural Formula VIIa-2: ,or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; X6, X7, and X8are each independently selected from CH2, CHF, CF2, C=O, or O; m is 1 or 2; n is 0 or 1; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl; R2is optionally substituted C1-C6 alkyl; and R3is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.In some embodiments, a compound of the present invention has the structure of Formula VI-or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein each D indicates a hydrogen having an isotopic enrichment factor for deuterium of at least 5.In some embodiments, a compound of the present invention has the structure of Formula VI-. Formula VI-II or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; R2is optionally substituted C1-C6 alkyl; and R3is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium. In some embodiments, a compound of the present invention has the structure of Formula VI-. Formula VI-V or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;R2is optionally substituted C1-C6 alkyl; and R3is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium. In some embodiments, a compound of the present invention has the structure of Formula VI- VI:. Formula VI-VI or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; R2is optionally substituted C1-C6 alkyl; and R3is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.In some embodiments, a compound of the present invention has the structure of Formula VI- VII:. Formula VI-VII or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; R2is optionally substituted C1-C6 alkyl; and R3is optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium. In some embodiments, a compound of the present invention has the structure of Formula VI- Va, Formula VI-Vb, Formula VI-Vc:Formula VI-Va,, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein each D indicates a hydrogen having an isotopic enrichment factor for deuterium of at least 5. In some embodiments, a compound of the present invention has the structure of Formula VI- Vd, Formula VI-Ve, Formula VI-Vf:Formula VI-Vd,, or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein each D indicates a hydrogen having an isotopic enrichment factor for deuterium of at least 5. In an aspect, the invention features a compound having the structure of Formula XI:, Formula XI or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein A is optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5 to6-membered heteroarylene, optionally substituted C2-C4 alkylene, or optionally substituted C2-C4 alkenylene; W is optionally substituted 3 to 10-membered heterocycloalkyl or optionally substituted 3 to 10-membered cycloalkyl; X4is CH2 or NH; R1is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6- membered cycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 3 to 15-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl; R2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3 to 6- membered cycloalkyl, optionally substituted 3 to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl; and R3is hydrogen; or R2and R3combine, together with the atoms to which they are attached, to form an optionally substituted 8- to 14-membered heterocycloalkyl; each of R4, R5, R6, and R7are hydrogen; or R4and R6are hydrogen and R5and R7combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl; or R5and R7are hydrogen and R4and R6combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl; R10is -OR11or -NR12R13; R11, R12, and R13are each, independently, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or R12and R13combine to form an optionally substituted 3- to 10- membered heterocycloalkyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3. In some embodiments, A is optionally substituted thiazole-diyl, optionally substituted oxazole- diyl, optionally substituted morpholine-diyl, optionally substituted pyrrolidine-diyl, optionally substituted piperidine-diyl, or optionally substituted phenylene. In some embodiments, A is optionally substituted thiazole-diyl or optionally substituted morpholine-diyl. In some embodiments of a compound of the present invention, A is optionally substituted 5- to 10-membered heteroarylene. In some embodiments, A is:. In some embodiments, A is. In some embodiments of a compound of the present invention, A is optionally substitutedIn some embodiments of a compound of the present invention, A is optionally substituted 3- to 6-membered heterocycloalkylene. In some embodiments, A is optionally substituted 6-membered heterocycloalkylene. In some embodiments, A is selected from the following, or a stereoisomerIn some embodiments of a compound of the present invention, R1is hydrogen, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl. In some embodiments of a compound of the present invention, R1is hydrogen or optionally substituted 3- to 10-membered heterocycloalkyl. In some embodiments of a compound of the present invention, R1is optionally substituted 3- to 10-membered heterocycloalkyl. In some embodiments of a compound ofIn some embodiments of a compound of the present invention, R1is:,, wherein each D indicates a hydrogen having an isotopic enrichment factor for deuterium of at least 5.In some embodiments of a compound of the present invention, R2is:. In some embodiments of a compound of the present invention, R2is:, ,and wherein each D indicates a hydrogen having an isotopic enrichment factor for deuterium of at least 5. In some embodiments of a compound of the present invention, R3is optionally substituted C1- C6 alkyl or optionally substituted 3- to 6-membered cycloalkyl. In some embodiments of a compound of the present invention, R3is optionally substituted C1-C6 alkyl. In some embodiments, R3is:wherein each D indicates a hydrogen having an isotopic enrichment factor for deuterium of at least 5. In some embodiments of a compound of the present invention, R3is or optionally substituted 3- to 6-membered cycloalkyl. In some embodiments, R3is:embodiments, R3is:.In some embodiments of a compound of the present invention, m is 1. In some embodiments, n is 1. In some embodiments, X1is CH2. In some embodiments, X2is CH2. In some embodiments, X3is CH2. In some embodiments, m is 1, n is 1, and each of X1, X2, and X3is CH2.In an aspect, the invention features a compound having the structure of Formula Ic:, Formula Ic or pharmaceutically acceptable salt, an enantiomer, a stereoisomer, or a tautomer thereof, wherein: Q is an optionally substituted 7- to 12- membered bicyclic arylene, an optionally substituted 7- to 12- membered bicyclic heteroarylene, an optionally substituted 7- to 12- membered bicyclic heterocyclylene, wherein a first ring in Q is bonded to X, and a second ring in Q is bonded to A; X is a bond; a straight chain C1-C3 alkylene optionally substituted with 1 to 3 substituents independently selected from fluoro, -CN, -C1-C3 alkyl, and -O-C1-C3 alkyl; -O-; -S(O)0-2-; *-CH2-O-; *-CH2-S(O)0-2-; *-O-CH2-; or *-CH2-S(O)0-2-, wherein “*” represents a portion of X bound to -C(R7)(R8)-; Y is -O-, -NH- or -N(C1-C3 alkyl)-; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; T is a second linker; R3is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, or optionally substituted 3- to 7- membered heterocyclyl; R10is hydrogen, halogen, optionally substituted C1-C3 alkyl, or C1-C3 optionally substituted heteroalkyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8is hydrogen, halogen, -OH, -CN, -O-(optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 4- to 8- membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7- membered heterocyclyl; or R7and R8together form =CH2, an optionally substituted C3-C6 cycloalkyl, or a 3- to 7- membered saturated heterocyclyl; or R8and a ring atom in Q, the carbon atom to which R7is bound, and X to form a 4- to 9- membered saturated or unsaturated heterocyclyl that is fused to Q; R6is hydrogen or -CH3;each R5is independently halogen, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 haloalkyl; p is 0, 1, 2, or 3; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl. In some embodiments of any of the compounds described herein, T has the structure of Formula XV:. Formula XV In some embodiments of Formula XV, z is 0. In some embodiments of any of the compounds described herein, T has the structure of Formula XVa:. Formula XVa In some embodiments, T has the structure of. In some embodiments, of Formula XV, z is 1. In some embodiments of any of the compounds described herein, T has the structure of Formula XVb:Formula XVbIn some embodiments of any of the compounds described herein, T has the structure of Formula XVc:. Formula XVc In some embodiments of any of the compounds described herein, T has the structure of Formula XVd: .Formula XVd In some embodiments of any of the compounds described herein, T has the structure of Formula XVe: .Formula XVe In some embodiments of Formula XV, z is 2. In some embodiments of any of the compounds described herein, T has the structure of Formula XVf: .Formula XVf In some embodiments, wherein RL1is hydrogen. In some embodiments, RL1is optionally substituted C1-C6 alkyl. In some embodiments, RL1is methyl, ethyl, or trifluoromethyl. In some embodiments, RL1is optionally substituted C1-C6 heteroalkyl. In some embodiments, RL1is methoxy or ethoxy. In some embodiments, RL1is optionally substituted C2-C6 alkynyl. In some embodiments, RL1is ethynyl. In some embodiments, RL2is hydrogen. In some embodiments, RL2is halogen. In some embodiments, RL2is fluoro.In some embodiments, RL3is hydrogen. In some embodiments, RL3is optionally substituted C1-C6 alkyl. In some embodiments, RL3is methyl. In some embodiments, RL4is hydrogen. In some embodiments, RL1and RL4combine to form an optionally substituted C4 cycloalkyl. In some embodiments, RL1and RL3combine to form an optionally substituted C4 cycloalkyl. In some embodiments, RL1and RL3combine to form an optionally substituted C5 cycloalkyl. In some embodiments, two RL1combine to form an optionally substituted C3-C6 cycloalkyl. In some embodiments, RL1and RL2combine to form an optionally substituted C3-C6 cycloalkyl. In some embodiments, T is:In some embodiments of any of the compounds described herein, T has the structure of Formula XVI:Formula XVI In some embodiments, X9is -NRL6-. In some embodiments of any of the compounds described herein, T has the structure of Formula XVIa:. Formula XVIa In some embodiments of any of the compounds described herein, T has the structure of Formula XVIb:. Formula XVIb In some embodiments, RL6is optionally substituted C1-C6 alkyl. In some embodiments, RL6is methyl. In some embodiments, X9is -C(O)-. In some embodiments, X9is -S(O)2-. In some embodiments, RL5is hydrogen. In some embodiments, RL5is optionally substituted C1-C6 alkyl. In some embodiments, RL5is optionally substituted C3-C8 cycloalkyl. In some embodiments, two RL5combine to form an optionally substituted C3-C8cycloalkyl.In some embodiments of any of the compounds described herein, T is:In some embodiments of any of the compounds described herein, T is:In some embodiments of any of the compounds described herein, T does not have the structure of:In some embodiments, L has the structure of Formula XIII: A1-(Z1)f-(C1)g-(Z2)h-(D1)-(Z3)i-(C2)j-(Z4)k–A2Formula XIII wherein A1is a bond between the linker and the rest of the macrocycle; A2is a bond between A and the linker; Z1, Z2, Z3, and Z4are each, independently, optionally substituted C1-C3 alkylene, optionally substituted C1-C3 heteroalkylene, optionally substituted C1-C2 alkenylene, optionally substituted 3- to 8-membered heterocycloalkylene, optionally substituted 3- to 8-membered cycloalkylene, O, NRNor a cross-linking group comprising a vinyl ketone, an ynone, a vinyl sulfone, an alkynyl sulfone, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, an aziridine, a trifluoromethyl ketone, a boronic acid, a boronic ester, an N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an iso- EEDQ or other EEDQ derivative, an epoxide, an oxazolium, or a glycal; RNis hydrogen, optionally substituted C1–C4 alkyl, or optionally substituted 6-membered arylene; C1and C2are each,independently, carbonyl or O; f, g, h, i, j, and k are each, independently, 0 or 1; and D1is optionally substituted C1-C2 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, optionally substituted 3- to 8-membered heterocycloalkylene, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted C1-C3 heteroalkylene, optionally substituted 6- membered arylene, or optionally substituted 5- to 10-membered heteroarylene, or a chemical bond linking A1-(Z1)f-(C1)g-(Z2)h- to -(Z3)i-(C2)j-(Z4)k–A2. In some embodiments of linkers of Formula XIII, f is 0. In some embodiments, f is 1. In some embodiments, g is 0. In some embodiments, g is 1. In some embodiments, h is 0. In some embodiments, h is 1. In some embodiments, i is 0. In some embodiments, j is 1. In some embodiments, k is 0. In some embodiments, k is 1. In some embodiments of linkers of Formula XIII, Z1is NRN. In some embodiments, RNis optionally substituted C1–C4 alkyl. In some embodiments, RNis methyl. In some embodiments of linkers of Formula XIII, C1is carbonyl. In some embodiments of linkers of Formula XIII, D1is 3- to 8-membered cycloalkylene. In some embodiments, D1is optionally substituted C1-C2 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, or optionally substituted C1-C3 heteroalkylene. In some embodiments, D1is optionally substituted 3- to 8-membered heterocycloalkylene. In some embodiments of linkers of Formula XIII, Z4is O. In some embodiments, Z4is optionally substituted C1-C3 alkylene. In some embodiments, Z3is optionally substituted C1-C3 alkylene. In some embodiments, L has the structure of Formula VIII:Formula VIII wherein X5is O or CH2 and is attached to ring A; and Z is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted C1-C6 alkylene, or optionally substituted C1-C6 heteroalkylene. In some embodiments of linkers of Formula VIII, X5is O. In some embodiments of linkers of Formula VIII, Z is optionally substituted 3- to 6-membered heterocycloalkylene. In some embodiments, Z is optionally substituted 5-membered heterocycloalkylene. In some embodiments, Z is optionally substituted pyrollidine-diyl. In some embodiments, L has the structure of Formula VIIIa:Formula VIIIa wherein X9is NR, O, or CH2 and is attached to ring A; X10is CH or N; X11is NR’’, O, C(O), C(O)N(R’’’)2, or CH2;R’’ is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R’’’, C(O)OR’’’, C(O)N(R’’’)2, S(O)R’’’, S(O)2R’’’, or S(O)2N(R’’’)2; each R’’’ is, independently, hydrogen, optionally substituted C1-C4 alkyl, or optionally substituted 3- to 6-membered heterocycloalkylene; R30and R32are, independently, hydrogen, optionally substituted C6-C10 aryl, or optionally substituted C1-C6 alkylene; R31is hydrogen, optionally substituted C6-C10 aryl, optionally substituted 4- to 8- membered heteroaryl, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted C1-C6 alkylene, or optionally substituted C1-C6 heteroalkylene; and q and r are, independently, 0, 1, 2, or 3. In some embodiments, L has the structure of Formula VIIIb:. Formula VIIIb In some embodiments, L has the structure of Formula VIIIc:. Formula VIIIc In some embodiments, L has the structure of Formula VIIId:. Formula VIIId In some embodiments, L has the structure of Formula VIIIe:. Formula VIIIe In some embodiments, L has the structure of Formula VIIIf:. Formula VIIIfIn some embodiments, L has the structure of Formula VIIIg:. Formula VIIIg In some embodiments of linkers of Formula VIIIa, the linker is:,In some embodiments, the linker has the following structure:wherein R37is hydrogen or substituted C1-C4 alkyl; R38is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted spirocyclic 8- to 11-membered heterocycloalkylene; and q is, 0, 1, 2, or 3. In some embodiments, the linker has the following structure:wherein R38is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted 3- to 7- membered heterocycloalkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6- membered cycloalkyl, or optionally substituted spirocyclic 8- to 11-membered heterocycloalkylene; and y and e are, independently, 1, 2, or 3. In some embodiments, the linker has a structure of Formula XII:, Formula XII wherein the left O atom is attached to ring A; R35is NR36C(O)CH2N(R36)2 or optionally substituted 3- to 6-membered heterocycloalkylene; and each R36is optionally substituted C1-C4 alkyl.In some embodiments, the linker has a structure of Formula XIV:Formula XIV wherein X5is O and is attached to ring A; each X13is, independently, O or NR34; and each R34is, independently, hydrogen or optionally substituted C1-C6 alkyl. In some embodiments, L has the structure of Formula IX:Formula IX wherein B is an optionally substituted 3- to 6-membered heterocycloalkylene; R22is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C6-C10 aryl,R23and R24are each, independently, hydrogen or optionally substituted C1-C6 alkyl; R25is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocyclyl; R26is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 6- membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted C6-C10 aryl; and R27is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C3-C10 cycloalkenyl, optionally substituted 3- to 10-membered heterocycloalkenyl, optionally substituted C6-C10 aryl, or optionally substituted 5- to 10-membered heteroaryl.In some embodiments, the linker of Formula IX has the structure of Formula X:Formula X In some embodiments of linkers of Formula IX or X, R22is . In some embodiments, R27is optionally substituted C1-C6 alkyl. In some embodiments, R27is optionally substituted C2-C6 alkenyl. In some embodiments, R27is optionally substituted C2-C6 alkynyl. In some embodiments, R27is optionally substituted C1-C6 heteroalkyl. In some embodiments, R27is optionally substituted C2-C6 heteroalkenyl. In some embodiments, R27is optionally substituted C2-C6 heteroalkynyl. In some embodiments, R27is optionally substituted C3-C10 cycloalkenyl. In some embodiments, R27is hydrogen. In some embodiments, R27is optionally substituted C3-C10 cycloalkyl. In some embodiments, R27is optionally substituted 3- to 10-membered heterocyclyl. In some embodiments of linkers of Formula IX or X, R22is. In some embodiments, R26is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R26is optionally substituted 3- to 10-membered heterocyclyl. In some embodiments of linkers of Formula IX or X, R22is optionally substituted 3- to 6- membered heterocyclyl. In some embodiments of compounds of Formula I, Formula II, Formula III, Formula IV, Formula IVa, Formula IVb, Formula IVc, Formula V, or Formula VI, A is optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene. In some embodiments, A is optionally substituted 6-membered arylene. In some embodiments, A is:. In any embodiment herein, a compound of the present invention may be modified with a substituent as found in any one or more of the following applications, incorporated herein by reference in their entireties: WO 2024 / 060966, WO 2024 / 017859, WO 2024 / 008834, WO 2024 / 008610, WO 2023 / 232776, WO 2023 / 208005, WO 2023 / 086341, WO 2023 / 025832, WO 2023 / 015559, CN 117720556, CN 117720555, CN 117720554, CN 117534687, CN 117534685 and CN 117534684.In some embodiments, a compound of the present invention is selected from Table 1, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, a compound of the present invention is selected from Table 1, or a pharmaceutically acceptable salt or atropisomer thereof. Table 1: Certain Compounds of the Present InventionAlso provided is a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Further provided is a conjugate, or salt thereof, of a compound of the present invention, wherein the compound of the present invention has a covalent warhead, bound to a monovalent organic moiety. In some embodiments of conjugates of the present invention, the monovalent organic moiety is a protein. In some embodiments, the protein is a Ras protein. In some embodiments, the Ras protein is K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, N-Ras G13C, K-Ras Q61H, H-Ras Q61H, N-Ras Q61H, N-Ras Q61K or N-Ras Q61R. Compounds of the present invention are also adaptable for uses in antibody-drug conjugates as well as degrader applications. Further provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. The cancer may, for example, be pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid gland adenocarcinoma, a myelodysplastic syndrome, or squamous cell lung carcinoma. In some embodiments, the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, or multiple myeloma. In some embodiments, the cancer comprises a Ras mutation, such as K-Ras Q61H, H-Ras Q61H, or N-Ras Q61H. Other Ras mutations are described herein. Further provided is a method of treating a Ras protein-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. Further provided is a method of inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. For example, the Ras protein is K-Ras Q61H, H-Ras Q61H, or N-Ras Q61H. Other Ras proteins are described herein. The cell may be a cancer cell, such as a pancreatic cancer cell, a colorectal cancer cell, a non-small cell lung cancer cell, an acute myeloid leukemia cell, a multiple myeloma cell, a thyroid gland adenocarcinoma cell, a myelodysplastic syndrome cell, or a squamous cell lung carcinoma cell. In some embodiments, the cell is a pancreatic cancer cell, a colorectal cancer cell, a non-small cell lung cancer cell, an acute myeloid leukemia cell,or a multiple myeloma cell, Other cancer types are described herein. The cell may be in vivo or in vitro. With respect to compounds of the present invention, one stereoisomer may exhibit better inhibition than another stereoisomer. For example, one atropisomer may exhibit inhibition, whereas the other atropisomer may exhibit little or no inhibition. In some embodiments, a method or use described herein further comprises administering an additional anti-cancer therapy. In some embodiments, the additional anti-cancer therapy is a HER2 inhibitor, an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, or a combination thereof. In some embodiments, the additional anticancer therapy is a SHP2 inhibitor. Other additional anti-cancer therapies are described herein. Methods of Synthesis The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic processes. The compounds of the present invention (see, e.g., compounds of Table 1) can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present invention can be synthesized using the methods described in the Schemes below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. As a further example, synthetic methods described in WO 2020 / 132597, WO 2021 / 091982, WO 2021 / 091967, WO 2021 / 091956, WO 2022 / 060836, WO 2022 / 235864, WO 2022 / 235870, WO 2023 / 060253, and WO 2023 / 133543, the disclosure of each of which is incorporated herein by reference, may be useful in preparing compounds of the invention. These methods include but are not limited to those methods described in the Schemes below.Scheme 1. General synthesis of functionalized bis-macrocyclesA general synthesis of functionalized bis-macrocycles is outlined in Scheme 1. An appropriately substituted biaryl intermediate (1) can be prepared in one step from an appropriately substituted 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylpropan-1-ol intermediate and an appropriately substituted methyl piperazic ester-containing aryl boronic ester by a palladium mediated coupling followed by ester hydrolysis. Macrolactonization followed by amine and phenol deprotection can yield macrocyclic ester (2). An appropriately substituted 2-(tosyloxymethyl)-3-(amido) cyclic amine (3) can be prepared by the coupling of an O-protected N-methyl-L-valine (4) with an appropriately substituted 2- (hydroxymethyl)-3-carboxylate cyclic amine using a peptide coupling reagent, followed by tosylation of the alcohol and carboxylic acid deprotection. The final functionalized bis-macrocycles can then be made by the peptide coupling of macrocyclic ester (1) with intermediate (3) followed by macrocyclic ether formation in the presence of base. Deprotection and coupling of the amine with an appropriately substituted carboxylic acid (or other coupling partner) results in a bis-macrocyclic product (5).Scheme 2. Alternative general synthesis of macrocyclic ester intermediate (2)Alternatively, macrocyclic ester intermediate (2) can be prepared as described in Scheme 2. An appropriately substituted aryl boronic ester (5) and be coupled with an appropriately protected 3- (5-bromo-indol-3-yl)-2,2-dimethylpropan-1-ol (6) in the presence of a palladium catalyst. This can be followed by indole iodination, alcohol deprotection, and ester hydrolysis. Subsequent coupling with methyl (S)-piperazic ester, ester hydrolysis and macrolactonization can result in iodinated macrocyclic intermediate (7). Coupling in the presence of palladium catalyst with an appropriately substituted aryl boronic ester (8) and indole N-alkylation, followed by subsequent amine and phenol deprotection result in intermediate (2). Scheme 3. General synthesis of functionalized amine bis-macrocyclesA general synthesis of functionalized bis-macrocycles is outlined in Scheme 3. An appropriately protected hydroxyalkyl amino acid can be coupled with O-protected N-methyl-L-valine (3) by a peptide coupling reagent. Subsequent alcohol and carboxylic acid deprotection can produce appropriately substituted intermediate (7). A protected amine bis-macrocyclic intermediate can be made by peptide coupling ofmacrocyclic ester intermediate (2) with carboxylic acid (7) followed by bis-macrocyclic ether formation in the presence of triphenylphosphine and an azodicarboxylate. Deprotection and coupling of the amine with an appropriately substituted carboxylic acid (or other coupling partner) results in final bis- macrocyclic product (8). Scheme 4. General synthesis of functionalized amine bis-macrocyclesA general synthesis of functionalized bis-macrocycles is outlined in Scheme 4. An appropriately substituted terminal alkyne (9) can be coupled with an appropriately substituted iodinated bromoarene (10) in the presence of a palladium catalyst. Subsequent reduction of aryl alkyne intermediate (11) followed by amino acid N-deprotection, carboxylic acid deprotection, macrocyclization in the presence of a peptide coupling reagent, ester hydrolysis, and peptide coupling with methyl (S)-piperazic ester can yield macrocyclic intermediate (12). Functionalized bis-macrocycle (13) can then be obtained through a palladium mediated coupling with an appropriately substituted 3- (5-boronate-indol-3-yl)-2,2-dimethylpropan-1-ol, macrolactonization, amine deprotection, and coupling of the amine with an appropriately substituted carboxylic acid (or other coupling partner). Scheme 5. General synthesis of functionalized amine bis-macrocyclesA general synthesis of functionalized bis-macrocycles is outlined in Scheme 5. An appropriately substituted 2-bromo-4-bromomethyl-5-ethenyl 5-membered heteroarene (14) can react with ethyl 2-((diphenylethylene)amino) acetate in the presence of base and a chiral auxiliary.Subsequent amide coupling with an appropriately substituted 2-(ethenyl)-3-(amido) cyclic amine (15) followed by an olefin metathesis reaction, ester hydrolysis, and an amide coupling reaction with methyl (S)-piperazic ester can yield macrocycle (16). Functionalized amine bis-macrocycle (17) can then be obtained through a palladium mediated coupling with an appropriately substituted 3-(5-boronate-indol-3-yl)-2,2-dimethylpropan-1-ol, methyl ester hydrolysis, macrolactonization, amine deprotection, and coupling of the amine with an appropriately substituted carboxylic acid (or other coupling partner). Scheme 6. General synthesis of functionalized amine bis-macrocyclesA general synthesis of functionalized bis-macrocycles is outlined in Scheme 6. An appropriately substituted iodinated bromoarene (10) can be coupled with a vinyl boronate ester in the presence of a palladium catalyst. Hydrolysis of the vinyl ether in the presence of acid can yield aldehyde (18). An appropriately N-functionalized O-protected amino acid (19) can be coupled with an aldehyde (18) in the presence of acid and a reducing agent. This can be followed by carboxylic acid deprotection and coupling of an O-protected N-methyl-L-valine (3) in the presence of an amide coupling reagent. Subsequent carboxylate and amine deprotections followed by cyclization in the presence of a peptide coupling reagent hydrolysis can yield macrocyclic intermediate (20). An appropriately substituted biaryl intermediate (21) can then be prepared in two steps through coupling of intermediate (20) with an appropriately substituted 3-(5-boronate-indol-3-yl)-2,2- dimethylpropan-1-ol by a palladium mediated coupling followed by ester hydrolysis. Subsequent coupling with methyl (S)-piperazic ester by a peptide coupling reagent, ester hydrolysis, and macrolactonization can yield functionalized amine bis-macrocycle (22).Scheme 7. General synthesis of functionalized bis-macrocyclesA general synthesis of functionalized bis-macrocycles is outlined in Scheme 7. An appropriately substituted biaryl intermediate (1) can be prepared in one step from an appropriately substituted 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylpropan-1-ol intermediate and an appropriately substituted methyl piperazic ester-containing aryl boronic ester by a palladium mediated coupling followed by ester hydrolysis. Macrolactonization followed by amine and phenol deprotection can yield macrocyclic ester (2). An appropriately substituted tosylated alcohol (4) can be prepared by the coupling of an O- protected N-methyl-L-valine (3) with an appropriately substituted hydroxyl carboxylate using a peptide coupling reagent, followed by tosylation of the alcohol and carboxylic acid deprotection. The final functionalized bis-macrocycles can then be made by the peptide coupling of macrocyclic ester (1) with intermediate (3) followed by macrocyclic ether formation in the presence of base. Deprotection and coupling of the amine with an appropriately substituted carboxylic acid (or other coupling partner) results in a bis-macrocyclic product (5).Scheme 8. General synthesis of functionalized amine bis-macrocyclesA general synthesis of functionalized bis-macrocycles is outlined in Scheme 8. An appropriately protected hydroxyalkyl carboxylic acid can be coupled with O-protected N-methyl-L- valine (3) by a peptide coupling reagent. Subsequent alcohol and carboxylic acid deprotection can produce appropriately substituted intermediate (7). A protected amine bis-macrocyclic intermediate can be made by peptide coupling of macrocyclic ester intermediate (2) with carboxylic acid (7) followed by bis-macrocyclic ether formation in the presence of triphenylphosphine and an azodicarboxylate. Deprotection and coupling of the amine with an appropriately substituted carboxylic acid (or other coupling partner) results in final bis- macrocyclic product (8). Scheme 9. General synthesis of functionalized amine bis-macrocyclesA general synthesis of functionalized bis-macrocycles is outlined in Scheme 9. An appropriately substituted terminal alkyne (9) can be coupled with an appropriately substituted iodinated bromoarene (10) in the presence of a palladium catalyst. Subsequent reduction of arylalkyne intermediate (11) followed by amino acid N-deprotection, carboxylic acid deprotection, macrocyclization in the presence of a peptide coupling reagent, ester hydrolysis, and peptide coupling with methyl (S)-piperazic ester can yield macrocyclic intermediate (12). Functionalized bis-macrocycle (13) can then be obtained through a palladium mediated coupling with an appropriately substituted 3- (5-boronate-indol-3-yl)-2,2-dimethylpropan-1-ol, macrolactonization, amine deprotection, and coupling of the amine with an appropriately substituted carboxylic acid (or other coupling partner). Scheme 10. General synthesis of functionalized amine bis-macrocyclesA general synthesis of functionalized bis-macrocycles is outlined in Scheme 10. An appropriately substituted 2-bromo-4-bromomethyl-5-ethenyl 5-membered heteroarene (14) can react with ethyl 2-((diphenylethylene)amino) acetate in the presence of base and a chiral auxiliary. Subsequent amide coupling with an appropriately substituted alkenyl valine (15) followed by an olefin metathesis reaction, ester hydrolysis, and an amide coupling reaction with methyl (S)-piperazic ester can yield macrocycle (16). Functionalized amine bis-macrocycle (17) can then be obtained through a palladium mediated coupling with an appropriately substituted 3-(5-boronate-indol-3-yl)-2,2-dimethylpropan-1-ol, methyl ester hydrolysis, macrolactonization, amine deprotection, and coupling of the amine with an appropriately substituted carboxylic acid (or other coupling partner).Scheme 11. General synthesis of functionalized bis-macrocyclesA general synthesis of functionalized bis-macrocycles is outlined in Scheme 1. An appropriately substituted biaryl intermediate (1) can be prepared in one step from an appropriately substituted 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylpropan-1-ol intermediate and an appropriately substituted methyl piperazic ester-containing aryl boronic ester by a palladium mediated coupling followed by ester hydrolysis. Macrolactonization followed by amine and phenol deprotection can yield macrocyclic ester (2). An appropriately substituted tosylated alcohol (4) can be prepared by the coupling of an O- protected N-methyl-L-valine (3) with an appropriately substituted hydroxyl carboxylate using a peptide coupling reagent, followed by tosylation of the alcohol and carboxylic acid deprotection. The final functionalized bis-macrocycles can then be made by the peptide coupling of macrocyclic ester (2) with intermediate (4) followed by macrocyclic ether formation in the presence of base. Deprotection and coupling of the amine with an appropriately substituted carboxylic acid (or other coupling partner) results in a bis-macrocyclic product (5).Scheme 12. General synthesis of functionalized bis-macrocyclesA general synthesis of functionalized bis-macrocycles is outlined in Scheme 2. An appropriately protected hydroxyalkyl carboxylic acid (6) can be coupled with O-protected N-methyl-L- valine (3) by a peptide coupling reagent. Subsequent alcohol and carboxylic acid deprotection can produce appropriately substituted intermediate (7). A bis-macrocyclic intermediate can be made by peptide coupling of macrocyclic ester intermediate (2) with carboxylic acid intermediate (7) followed by bis-macrocyclic ether formation in the presence of triphenylphosphine and an azodicarboxylate. Deprotection and coupling of the amine with an appropriately substituted carboxylic acid (or other coupling partner) results in final bis- macrocyclic product (8). Scheme 13. General synthesis of functionalized bis-macrocyclesA general synthesis of functionalized bis-macrocycles is outlined in Scheme 3. An appropriately substituted terminal alkyne (9) can be coupled with an appropriately substituted iodinated bromoarene (10) in the presence of a palladium catalyst. Subsequent reduction of arylalkyne intermediate (11) followed by amino acid N-deprotection, carboxylic acid deprotection, macrocyclization in the presence of a peptide coupling reagent, ester hydrolysis, and peptide coupling with methyl (S)-piperazic ester can yield macrocyclic intermediate (12). Functionalized bis-macrocycle (13) can then be obtained through a palladium mediated coupling with an appropriately substituted 3- (5-boronate-indol-3-yl)-2,2-dimethylpropan-1-ol, macrolactonization, amine deprotection, and coupling of the amine with an appropriately substituted carboxylic acid (or other coupling partner). Scheme 14. General synthesis of functionalized bis-macrocyclesA general synthesis of functionalized bis-macrocycles is outlined in Scheme 4. An appropriately substituted 2-bromo-4-bromomethyl-5-ethenyl 5-membered heteroarene (14) can react with ethyl 2-((diphenylethylene)amino) acetate in the presence of base and a chiral auxiliary. Subsequent amide coupling with an appropriately substituted alkenyl valine (15) followed by an olefin metathesis reaction, ester hydrolysis, and an amide coupling reaction with methyl (S)-piperazic ester can yield macrocycle (16). Functionalized bis-macrocycle (17) can then be obtained through a palladium mediated coupling with an appropriately substituted 3-(5-boronate-indol-3-yl)-2,2-dimethylpropan-1-ol, methyl ester hydrolysis, macrolactonization, amine deprotection, and coupling of the amine with an appropriately substituted carboxylic acid (or other coupling partner).Scheme 15. General synthesis of functionalized bis-macrocyclesA general synthesis of functionalized bis-macrocycles is outlined in Scheme 5. An appropriately substituted iodinated bromoarene (10) can be coupled with a vinyl boronate ester in the presence of a palladium catalyst. Hydrolysis of the vinyl ether in the presence of acid can yield aldehyde (18). An appropriately N-functionalized O-protected amino acid (19) can be coupled with aldehyde (18) in the presence of acid and a reducing agent. This can be followed by carboxylic acid deprotection and coupling of an O-protected N-methyl-L-valine (3) in the presence of an amide coupling reagent. Subsequent carboxylate and amine deprotections followed by cyclization in the presence of a peptide coupling reagent can yield macrocyclic intermediate (20). An appropriately substituted biaryl intermediate (21) can then be prepared in two steps through coupling of intermediate (20) with an appropriately substituted 3-(5-boronate-indol-3-yl)-2,2- dimethylpropan-1-ol by a palladium mediated coupling followed by ester hydrolysis. Subsequent coupling with methyl (S)-piperazic ester by a peptide coupling reagent, ester hydrolysis, and macrolactonization can yield functionalized amine bis-macrocycle (22).Scheme 16. General synthesis of functionalized bis-macrocyclesA general synthesis of functionalized bis-macrocycles is outlined in Scheme 6. An appropriately substituted vinyl bromoarene (23) can be coupled with an appropriately functionalized O-protected carboxylic acid containing a terminal alkene (24) in the presence of an olefin metathesis catalyst. Subsequent carboxylic acid deprotection and amine deprotection followed by intramolecular coupling in the presence of a peptide coupling reagent can yield mono-macrocyclic intermediate (25). An appropriately substituted biaryl intermediate (26) can then be prepared in two steps through coupling of intermediate (25) with an appropriately substituted 3-(5-boronate-indol-3-yl)-2,2- dimethylpropan-1-ol by a palladium mediated coupling followed by ester hydrolysis. Alkene reduction in the presence of H2 and an appropriate transition metal hydrogenation catalyst followed by ester hydrolysis can yield intermediate (27). Subsequent coupling with methyl (S)-piperazic ester by a peptide coupling reagent, ester hydrolysis, and macrolactonization can yield functionalized bis- macrocycle (28). Scheme 17. General synthesis of functionalized bis-macrocyclesA general synthesis of functionalized bis-macrocycles is outlined in Scheme 7. An appropriately substituted aniline macrocycle (29) can be coupled with an appropriately functionalized O-protected carboxylic acid containing an aldehyde (30) by a reductive amination in the presence of acid and a reducing agent to form intermediate (31). Subsequent carboxylate and amine deprotections followed by macrocyclization in the presence of a peptide coupling reagent can yield functionalized aniline bis-macrocycle (32).Scheme 18. General synthesis of functionalized bis-macrocyclesA general synthesis of functionalized bis-macrocycles is outlined in Scheme 8. An appropriately substituted aniline macrocycle (29) can be coupled with an appropriately functionalized O-protected carboxylic acid containing a tosylate (33) in the presence of base to form intermediate (34). Subsequent carboxylate and amine deprotections followed by macrocyclization in the presence of a peptide coupling reagent can yield aniline bis-macrocycle (35). Scheme 19. General synthesis of functionalized bis-macrocyclesA general synthesis of functionalized bis-macrocycles is outlined in Scheme 9. An appropriately substituted benzaldehyde macrocycle (36) can be coupled with an appropriately functionalized O-protected carboxylic acid containing an amine (37) through a reductive amination in the presence of acid and a reducing agent to form intermediate (38). Subsequent carboxylate and amine deprotections followed by macrocyclization in the presence of a peptide coupling reagent can yield functionalized benzylic amine bis-macrocycle (39). In any embodiment herein, a compound of the present invention may be modified with a substituent as found in any one or more of the following applications using methodologies described in these applications in combination with methods provided herein and know to those of skill in the art: WO 2024 / 060966, WO 2024 / 017859, WO 2024 / 008834, WO 2024 / 008610, WO 2023 / 232776, WO 2023 / 208005, WO 2023 / 086341, WO 2023 / 025832, WO 2023 / 015559, CN 117720556, CN 117720555, CN 117720554, CN 117534687, CN 117534685 and CN 117534684, each incorporated herein by reference in their entireties. Pharmaceutical Compositions and Methods of Use The compounds with which the invention is concerned are Ras inhibitors and are useful in the treatment of cancer. Accordingly, one embodiment of the present invention provides pharmaceutical compositions containing a compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, as well as methods of using the compounds of the invention to prepare such compositions.As used herein, the term “pharmaceutical composition” refers to a compound, such as a compound of the present invention, or a pharmaceutically acceptable salt thereof, formulated together with a pharmaceutically acceptable excipient. In some embodiments, a compound is present in a pharmaceutical composition in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces. A “pharmaceutically acceptable excipient,” as used herein, refers to any inactive ingredient (for example, a vehicle capable of suspending or dissolving the active compound) having the properties of being nontoxic and non-inflammatory in a subject. Typical excipients include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration. Excipients include, but are not limited to: butylated optionally substituted hydroxyltoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxylpropyl cellulose, optionally substituted hydroxylpropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those of ordinary skill in the art are familiar with a variety of agents and materials useful as excipients. See, e.g., e.g., Ansel, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. In some embodiments, a composition includes at least two different pharmaceutically acceptable excipients. Compounds described herein, whether expressly stated or not, may be provided or utilized in salt form, e.g., a pharmaceutically acceptable salt form, unless expressly stated to the contrary. The term “pharmaceutically acceptable salt,” as use herein, refers to those salts of the compounds described herein that are, within the scope of sound medical judgment, suitable for use in contact withthe tissues of humans and other animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid. The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention, be prepared from inorganic or organic bases. In some embodiments, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well-known in the art, such as hydrochloric, sulfuric, hydrobromic, acetic, lactic, citric, or tartaric acids for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, and the like for forming basic salts. Methods for preparation of the appropriate salts are well-established in the art. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-optionally substituted hydroxyl-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. As used herein, the term “subject” refers to any member of the animal kingdom. In some embodiments, “subject” refers to humans, at any stage of development. In some embodiments, “subject” refers to a human patient. In some embodiments, “subject” refers to non-human animals. In some embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig). In some embodiments, subjects include, but are not limited to, mammals, birds, reptiles, amphibians, fish, or worms. In some embodiments, a subject may be a transgenic animal, genetically-engineered animal, or a clone. As used herein, the term “dosage form” refers to a physically discrete unit of a compound (e.g., a compound of the present invention) for administration to a subject. Each unit contains a predetermined quantity of compound. In some embodiments, such quantity is a unit dosage amount(or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen). Those of ordinary skill in the art appreciate that the total amount of a therapeutic composition or compound administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms. As used herein, the term “dosing regimen” refers to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic compound (e.g., a compound of the present invention) has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen). A “therapeutic regimen” refers to a dosing regimen whose administration across a relevant population is correlated with a desired or beneficial therapeutic outcome. The term “treatment” (also “treat” or “treating”), in its broadest sense, refers to any administration of a substance (e.g., a compound of the present invention) that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, or reduces incidence of one or more symptoms, features, or causes of a particular disease, disorder, or condition. In some embodiments, such treatment may be administered to a subject who does not exhibit signs of the relevant disease, disorder, or condition or of a subject who exhibits only early signs of the disease, disorder, or condition. Alternatively, or additionally, in some embodiments, treatment may be administered to a subject who exhibits one or more established signs of the relevant disease, disorder, or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, or condition. The term “therapeutically effective amount” means an amount that is sufficient, when administered to a population suffering from or susceptible to a disease, disorder, or condition in accordance with a therapeutic dosing regimen, to treat the disease, disorder, or condition. In some embodiments, a therapeutically effective amount is one that reduces the incidence or severity of, or delays onset of, one or more symptoms of the disease, disorder, or condition. Those of ordinary skillin the art will appreciate that the term “therapeutically effective amount” does not in fact require successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be that amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment. It is specifically understood that particular subjects may, in fact, be “refractory” to a “therapeutically effective amount.” In some embodiments, reference to a therapeutically effective amount may be a reference to an amount as measured in one or more specific tissues (e.g., a tissue affected by the disease, disorder, or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those of ordinary skill in the art will appreciate that, in some embodiments, a therapeutically effective amount may be formulated or administered in a single dose. In some embodiments, a therapeutically effective amount may be formulated or administered in a plurality of doses, for example, as part of a dosing regimen. For use as treatment of subjects, the compounds of the invention, or a pharmaceutically acceptable salt thereof, can be formulated as pharmaceutical or veterinary compositions. Depending on the subject to be treated, the mode of administration, and the type of treatment desired, e.g., prevention, prophylaxis, or therapy, the compounds, or a pharmaceutically acceptable salt thereof, are formulated in ways consonant with these parameters. A summary of such techniques may be found in Remington: The Science and Practice of Pharmacy, 21stEdition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference. Compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of a compound of the present invention, or pharmaceutically acceptable salt thereof, by weight or volume. In some embodiments, compounds, or a pharmaceutically acceptable salt thereof, described herein may be present in amounts totaling 1-95% by weight of the total weight of a composition, such as a pharmaceutical composition. The composition may be provided in a dosage form that is suitable for intraarticular, oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intravesicular, intraurethral, intrathecal, epidural, aural, or ocular administration, or by injection, inhalation, or direct contact with the nasal, genitourinary, reproductive, or oral mucosa. Thus, the pharmaceutical composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, preparations suitable for iontophoretic delivery, or aerosols. The compositions may be formulated according to conventional pharmaceutical practice. As used herein, the term “administration” refers to the administration of a composition (e.g., a compound, or a preparation that includes a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, in some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal,intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, or vitreal. Formulations may be prepared in a manner suitable for systemic administration or topical or local administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection) or may be prepared for transdermal, transmucosal, or oral administration. A formulation will generally include a diluent as well as, in some cases, adjuvants, buffers, preservatives and the like. Compounds, or a pharmaceutically ...

Claims

Claims 1. A compound selected from Formula Ia, Formula Ib, Formula IIa, Formula IIb, Formula IIa-1, Formula IIIa, Formula IIIb, Formula IIIa-1, Formula IVa, Formula IVb, Formula Va, Formula Vb, Formula VIa, Formula VIb, Formula VIIa, Formula VIIb, or Formula XI, or a pharmaceutically acceptable salt thereof, wherein Formula Ia has the structure of:, Formula Ia wherein: Q is an optionally substituted 7- to 12- membered bicyclic arylene, an optionally substituted 7- to 12- membered bicyclic heteroarylene, an optionally substituted 7- to 12- membered bicyclic heterocyclylene, wherein a first ring in Q is bonded to X, and a second ring in Q is bonded to A; X is a bond; a straight chain C1-C3 alkylene optionally substituted with 1 to 3 substituents independently selected from fluoro, -CN, -C1-C3 alkyl, and -O-C1-C3 alkyl; -O-; -S(O)0-2-; *-CH2-O-; *-CH2-S(O)0-2-; *-O-CH2-; or *-CH2-S(O)0-2-, wherein “*” represents a portion of X bound to -C(R7)(R8)-; Y is -O-, -NH- or -N(C1-C3 alkyl)-; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; R3is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, or optionally substituted 3- to 7- membered heterocyclyl; R10is hydrogen, halogen, optionally substituted C1-C3 alkyl, or C1-C3 optionally substituted heteroalkyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8is hydrogen, halogen, -OH, -CN, -O-(optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 4- to 8- membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7- membered heterocyclyl; orR7and R8together form =CH2, an optionally substituted C3-C6 cycloalkyl, or a 3- to 7- membered saturated heterocyclyl; or R8and a ring atom in Q, the carbon atom to which R7is bound, and X to form a 4- to 9- membered saturated or unsaturated heterocyclyl that is fused to Q; R6is hydrogen or -CH3; each R5is independently halogen, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 haloalkyl; p is 0, 1, 2, or 3; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; wherein Formula Ib has the structure of:, Formula Ib wherein: Q is an optionally substituted 7- to 12- membered bicyclic arylene, an optionally substituted 7- to 12- membered bicyclic heteroarylene, an optionally substituted 7- to 12- membered bicyclic heterocyclylene, wherein a first ring in Q is bonded to X, and a second ring in Q is bonded to A; X is a bond; a straight chain C1-C3 alkylene optionally substituted with 1 to 3 substituents independently selected from fluoro, -CN, -C1-C3 alkyl, and -O-C1-C3 alkyl; -O-; -S(O)0-2-; *-CH2-O-; *-CH2-S(O)0-2-; *-O-CH2-; or *-CH2-S(O)0-2-, wherein “*” represents a portion of X bound to -C(R7)(R8)-; Y is -O-, -NH- or -N(C1-C3 alkyl)-; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker;R3is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, or optionally substituted 3- to 7- membered heterocyclyl; R10is hydrogen, halogen, optionally substituted C1-C3 alkyl, or C1-C3 optionally substituted heteroalkyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8is hydrogen, halogen, -OH, -CN, -O-(optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 4- to 8- membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7- membered heterocyclyl; or R7and R8together form =CH2, an optionally substituted C3-C6 cycloalkyl, or a 3- to 7- membered saturated heterocyclyl; or R8and a ring atom in Q, the carbon atom to which R7is bound, and X to form a 4- to 9- membered saturated or unsaturated heterocyclyl that is fused to Q; R6is hydrogen or -CH3; each R5is independently halogen, optionally substituted C1-C3 alkyl, or optionally substituted C1-C3 haloalkyl; p is 0, 1, 2, or 3; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; wherein Formula IIa has the structure of:, Formula IIaor a pharmaceutically acceptable salt thereof, wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9’, or >CR9R9’where the carbon is bound to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R6)- where C is bound to -C(R7R8)-, -C(O)NH-CH(R6)- where C is bound to -C(R7R8)-, optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is a linker; X3is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; each R’is, independently, hydrogen or optionally substituted C1-C4 alkyl; Y1is C, CH, or N; Y2, Y3, Y4, and Y7are, independently, C or N; Y5is CRx, CH, CH2, or N; Y6is CRz, C(O), CH, CH2, or N; Rxis hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; Rzis hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; R13is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R13and R2combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R2is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl;R14is absent, or R2and R14combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 heteroalkyl, cyclopropyl, or cyclobutyl; R6is hydrogen or methyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6and R7combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7and R8combine with the carbon atom to which they are attached to form C=CR7’R8’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7aand R8aare, independently, hydrogen, halogen, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7’is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10- membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7’and R8’combine with the carbon atom to which they are attached to form optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R9and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9’is hydrogen or optionally substituted C1-C6 alkyl; or R9and R9’, combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10is hydrogen, halogen, hydroxy, optionally substituted C1-C3 heteroalkyl, or optionally substituted C1-C3 alkyl; R10ais hydrogen or halogen; R11is hydrogen or optionally substituted C1-C3 alkyl; R21is hydrogen or optionally substituted C1-C3 alkyl; z is 0, 1, or 2;X9is -NRL6-, -C(O)-, or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; wherein Formula IIb has the structure of:, Formula IIb or a pharmaceutically acceptable salt thereof, wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9’, or >CR9R9’where the carbon is bound to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R6)- where C is bound to -C(R7R8)-, -C(O)NH-CH(R6)- where C is bound to -C(R7R8)-, optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is a linker; X3is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; each R’is, independently, hydrogen or optionally substituted C1-C4 alkyl; Y1is C, CH, or N;Y2, Y3, Y4, and Y7are, independently, C or N; Y5is CRx, CH, CH2, or N; Y6is CRz, C(O), CH, CH2, or N; Rxis hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; Rzis hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; R13is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R13and R2combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R2is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R14is absent, or R2and R14combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 heteroalkyl, cyclopropyl, or cyclobutyl; R6is hydrogen or methyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6and R7combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7and R8combine with the carbon atom to which they are attached to form C=CR7’R8’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7aand R8aare, independently, hydrogen, halogen, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7’is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionallysubstituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10- membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7’and R8’combine with the carbon atom to which they are attached to form optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R9and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9’is hydrogen or optionally substituted C1-C6 alkyl; or R9and R9’, combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10is hydrogen, halogen, hydroxy, optionally substituted C1-C3 heteroalkyl, or optionally substituted C1-C3 alkyl; R10ais hydrogen or halogen; R11is hydrogen or optionally substituted C1-C3 alkyl; R21is hydrogen or optionally substituted C1-C3 alkyl; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; wherein Formula IIa-1 has the structure of:, Formula IIa-1or a pharmaceutically acceptable salt thereof, wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds; A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; B is absent, -CH(R9)-, >C=CR9R9’, or >CR9R9’where the carbon is bound to the carbonyl carbon of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R6)- where C is bound to -C(R7R8)-, -C(O)NH-CH(R6)- where C is bound to -C(R7R8)-, optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is a linker; X1is optionally substituted C1-C2 alkylene, NR, O, or S(O)q; X2is O or NH; X3is N or CH; q is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R’, C(O)OR’, C(O)N(R’)2, S(O)R’, S(O)2R’, or S(O)2N(R’)2; each R’is, independently, hydrogen or optionally substituted C1-C4 alkyl; Y1is C, CH, or N; Y2, Y3, Y4, and Y7are, independently, C or N; Y5is CRx, CH, CH2, or N; Y6is CRz, C(O), CH, CH2, or N; Rxis hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; Rzis hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; R13is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10- membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R13and R2combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R2is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionallysubstituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R14is absent, or R2and R14combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R15is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 heteroalkyl, cyclopropyl, or cyclobutyl; R6is hydrogen or methyl; R7is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6and R7combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7and R8combine with the carbon atom to which they are attached to form C=CR7’R8’; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7aand R8aare, independently, hydrogen, halogen, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7’is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10- membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7’and R8’combine with the carbon atom to which they are attached to form optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R9and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9’is hydrogen or optionally substituted C1-C6 alkyl; or R9and R9’, combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10is hydrogen, halogen, hydroxy, optionally substituted C1-C3 heteroalkyl, or optionally substituted C1-C3 alkyl; R10ais hydrogen or halogen; R11is hydrogen or optionally substituted C1-C3 alkyl; andR21is hydrogen or optionally substituted C1-C3 alkyl; wherein Formula IIIa has the structure of:, Formula IIIa or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4, , or ; L is a linker; R13is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl;R10is hydrogen, hydroxy, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7and R8are each, independently, selected from F or CH3, or R7and R8combine with the atoms to which they are attached to make a 3-membered cycloalkyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; t is 0, 1, 2, or 3; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; wherein Formula IIIb has the structure of:, Formula IIIb or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene;, , or ; L is a linker; R13is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R10is hydrogen, hydroxy, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7and R8are each, independently, selected from F or CH3, or R7and R8combine with the atoms to which they are attached to make a 3-membered cycloalkyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; t is 0, 1, 2, or 3; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; and each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl;wherein Formula IIIa-1 has the structure of:, Formula IIIa-1 or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4alkylene, optionally substituted C1-C4heteroalkylene or optionally substituted C2-C4alkenylene;, , or ; L is a linker; X4and X5are each, independently, CH2, CH(CH3) or NH; R13is optionally substituted C1-C6alkyl, optionally substituted C1-C6heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R10is hydrogen, hydroxy, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;R7and R8are each, independently, selected from F or CH3, or R7and R8combine with the atoms to which they are attached to make a 3-membered cycloalkyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3; wherein Formula IVa has the structure of:, Formula IVa or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl; R2is optionally substituted C1-C6alkyl; R3is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; andt is 0, 1, 2, or 3; wherein Formula IVb has the structure of:, Formula IVb or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl; R2is optionally substituted C1-C6 alkyl; R3is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; andt is 0, 1, 2, or 3; wherein Formula Va has the structure of:, Formula Va or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; R1is hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl; R2is optionally substituted C1-C6 alkyl; R3is optionally substituted C1-C6alkyl or optionally substituted C1-C3heteroalkyl; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3;wherein Formula Vb has the structure of:, Formula Vb or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl; R2is optionally substituted C1-C6 alkyl; R3is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3;wherein Formula VIa has the structure of:, Formula VIa or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; W is a cross-linking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, an N-ethoxycarbonyl-2- ethoxy-1,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium, or a glycal; X6is CH2 or O; m is 1 or 2; n is 0 or 1; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl; R2is optionally substituted C1-C6 alkyl; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3;wherein Formula VIb has the structure of:, Formula VIb or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; W is a cross-linking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, an N-ethoxycarbonyl-2- ethoxy-1,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium, or a glycal; X6is CH2 or O; m is 1 or 2; n is 0 or 1; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl; R2is optionally substituted C1-C6 alkyl; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3;wherein Formula VIIa has the structure of:, Formula VIIa or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; X6, X7, and X8are each independently selected from CH2, CHF, CF2, C=O, or O; m is 1 or 2; n is 0 or 1; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl; R2is optionally substituted C1-C6 alkyl; R3is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3;wherein Formula VIIb has the structure of:, Formula VIIb or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6- membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; L is a linker; X6, X7, and X8are each independently selected from CH2, CHF, CF2, C=O, or O; m is 1 or 2; n is 0 or 1; R1is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl; R2is optionally substituted C1-C6 alkyl; R3is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium; z is 0, 1, or 2; X9is -NRL6-, -C(O)-, or -S(O)2-; each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C1-C6 heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; and t is 0, 1, 2, or 3; andwherein Formula XI has the structure of:, Formula XI or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3 to 6- membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5 to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, or optionally substituted C2-C4 alkenylene; W is optionally substituted 3 to 10-membered heterocycloalkyl or optionally substituted 3 to 10-membered cycloalkyl; X4is CH2 or NH; R1is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6- membered cycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 3 to 15-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl; R2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3 to 6- membered cycloalkyl, optionally substituted 3 to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl; and R3is hydrogen; or R2and R3combine, together with the atoms to which they are attached, to form an optionally substituted 8- to 14-membered heterocycloalkyl; each of R4, R5, R6, and R7are hydrogen; or R4and R6are hydrogen and R5and R7combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl; or R5and R7are hydrogen and R4and R6combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl; R10is -OR11or -NR12R13; R11, R12, and R13are each, independently, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or R12and R13combine to form an optionally substituted 3- to 10- membered heterocycloalkyl; each R33is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl; andt is 0, 1, 2, or 3.

2. A compound, or a pharmaceutically acceptable salt thereof, of Table 1.

3. A pharmaceutical composition comprising a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

4. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 3.

5. A method of treating a Ras protein-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 3.

6. A method of inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 3.

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